Self-Organization and Information Processing: from Basic Enzymatic Activities to Complex Adaptive Cellular Behavior

gene-12-644615 May 15, 2021 Time: 15:2 # 1
REVIEW
published: 21 May 2021
doi: 10.3389/ gene.2021.644615
Edi ed by:
Julian Gonzalez Ayala,
Uni e si y o Salamanca, Spain
Re iewed by:
Mehdi Sadeghi,
Semnan Uni e si y, I an
Moisés San illán,
Cen o de In es igaciones y Es udios
A anzados, Ins i u o Poli écnico
Nacional de México (CINVESTAV),
Mexico
*Co espondence:
Ilde onso M. De la Fuen e
[email p o ec ed];
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
E olu iona y and Popula ion Gene ics,
a sec ion o he jou nal
F on ie s in Gene ics
Recei ed: 21 Decembe 2020
Accep ed: 16 Ap il 2021
Published: 21 May 2021
Ci a ion:
De la Fuen e IM, Ma ínez L,
Ca asco-Pujan e J, Fede z M,
López JI and Malaina I (2021)
Sel -O ganiza ion and In o ma ion
P ocessing: F om Basic Enzyma ic
Ac i i ies o Complex Adap i e
Cellula Beha io .
F on . Gene . 12:644615.
doi: 10.3389/ gene.2021.644615
Sel -O ganiza ion and In o ma ion
P ocessing: F om Basic Enzyma ic
Ac i i ies o Complex Adap i e
Cellula Beha io
Ilde onso M. De la Fuen e1,2*, Luis Ma ínez2,3, Jose Ca asco-Pujan e4, Ma ia Fede z5,
José I. López6and Ike Malaina2
1Depa men o Nu i ion, CEBAS-CSIC Ins i u e, Mu cia, Spain, 2Depa men o Ma hema ics, Facul y o Science
and Technology, Uni e si y o he Basque Coun y, UPV/EHU, Leioa, Spain, 3Basque Cen e o Applied Ma hema ics
(BCAM), Bilbao, Spain, 4Depa men o Cell Biology and His ology, Facul y o Medicine and Nu sing, Uni e si y o he
Basque Coun y, UPV/EHU, Leioa, Spain, 5Depa men o Cell Biology and Immunology, Ins i u e o Pa asi ology
and Biomedicine “López-Ney a”, CSIC, G anada, Spain, 6Depa men o Pa hology, C uces Uni e si y Hospi al,
Bioc uces-Bizkaia Heal h Resea ch Ins i u e, Ba akaldo, Spain
One o he main aims o cu en biology is o unde s and he o igin o he molecula
o ganiza ion ha unde lies he complex dynamic a chi ec u e o cellula li e. He e,
we p esen an o e iew o he main sou ces o biomolecula o de and complexi y
spanning om he mos elemen a y le els o molecula ac i i y o he eme gence o
cellula sys emic beha io s. Fi s , we ha e add essed he dissipa i e sel -o ganiza ion,
he p incipal sou ce o molecula o de in he cell. In ensi e s udies o e he las ou
decades ha e demons a ed ha sel -o ganiza ion is cen al o unde s and enzyme
ac i i y unde cellula condi ions, unc ional coo dina ion be ween enzyma ic eac ions,
he eme gence o dissipa i e me abolic ne wo ks (DMN), and molecula hy hms. The
second undamen al sou ce o o de is molecula in o ma ion p ocessing. S udies
on e ec i e connec i i y based on ans e en opy (TE) ha e made possible he
quan i ica ion in bi s o biomolecula in o ma ion lows in DMN. This in o ma ion
p ocessing enables e icien sel - egula o y con ol o me abolism. As a consequence
o bo h main sou ces o o de , sys emic unc ional s uc u es eme ge in he cell; in
ac , quan i a i e analyses wi h DMN ha e e ealed ha he basic uni s o li e display
a global enzyma ic s uc u e ha seems o be an essen ial cha ac e is ic o he sys emic
unc ional me abolism. This global me abolic s uc u e has been e i ied expe imen ally
in bo h p oka yo ic and euka yo ic cells. He e, we also discuss how he s udy o
sys emic DMN, using A i icial In elligence and ad anced ools o S a is ic Mechanics,
has shown he eme gence o Hop ield-like dynamics cha ac e ized by exhibi ing
associa i e memo y. We ha e ecen ly con i med his hesis by es ing associa i e
condi ioning beha io in indi idual amoeba cells. In hese Pa lo ian-like expe imen s,
se e al hund eds o cells could lea n new sys emic mig a o y beha io s and emembe
hem o e long pe iods ela i e o hei cell cycle, o ge ing hem la e . Such associa i e
p ocess seems o co espond o an epigene ic memo y. The cellula capaci y o lea ning
new adap i e sys emic beha io s ep esen s a undamen al e olu iona y mechanism o
cell adap a ion.
Keywo ds: en opy, dissipa i e s uc u es, sel -o ganiza ion, Hop ield dynamics, in o ma ion p ocessing
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
INTRODUCTION
The cell is a highly sel -o ganized dynamic molecula sys em ha
cons i u es he basic undamen al uni o all known li e o ms.
A b eak h ough has been made in he knowledge o he
cellula molecula componen s and unde s anding he basic
mechanisms o many o hei in e ac ions. Howe e , we s ill do
no know many o he essen ial aspec s o he highly sel -o de ed
dynamics ha cha ac e ize he biochemical li e o cells.
All molecula componen s o cells exhibi complex chemical
ans o ma ions shaping an ex eme supe complex sys em,
whe e simul aneously he concen a ions o millions o ions and
molecules change pe manen ly ollowing high-o de ed pa e ns,
s uc u ed in space and in ime.
The consequences o hese incessan sel -o ganized and sel -
egula ed dynamics o eac i e molecula ans o ma ions a e
adequa e cellula g ow h, he de elopmen o all physiological
p ocesses o main ain i s unc ional s uc u es, con inuous
adap a ion o he en i onmen , and, las ly, mi osis. Al e a ions in
hese sel -o ganized dynamics lead o di e en pa hologies and,
on ce ain occasions, he dynamic o de collapses and cell dies.
The limi a ions in he s udy o cellula molecula dynamics
by adi ional me hods ha e been compensa ed by he e o s o
quan i a i e sciences applied o Biology, especially Sys ems
Biology. Physical-ma hema ical app oaches a e making
possible o unde s and he p inciples unde lying he complex
cellula molecula dynamics adequa ely, so concep s such
as sel -o ganized dissipa i e s uc u es, sel - egula ion, he
eme gence o unc ional p ope ies, sys emic a ac o s, and
in o ma ion p ocessing, a e pa o he new landscape o
con empo a y biology.
In ligh o hese quan i a i e ad ances, each cell is no
a me e molecula agg ega e bu a supe complex dynamic
sys em whe e highly sel -o de ed dissipa i e pa e ns, he main
sou ce o molecula o de in he cell, do eme ge oge he
wi h sel - egula o y beha io s o igina ed by biomolecula
in o ma ion p ocessing, ano he undamen al sou ce o
o ganiza ion in he cell.
He e, we p esen an o e iew o he main sou ces o
biomolecula o de and complexi y ha unde line he
molecula dynamics o cells. These sou ces span om he
mos elemen a y le els o molecula ac i i y o he eme gence o
sys emic beha io s.
- In he “The Dynamics O igina ed by he Molecula
Tu no e and he Role o he Enzymes in These Supe
Complex Dynamics” sec ion, we ha e app oached wo
undamen al issues: he dynamics o igina ed by he
molecula u no e o cells and he ole o he enzymes in
hese supe complex dynamics.
All molecula componen s o he cell a e syn hesized and
deg aded con inually ollowing sophis ica ed in e dependen
p ocesses ha de y he human in ellec . This con inuous
molecula u no e is p oduced by a supe complex dynamic
sys em o med by millions o biochemical eac ions, which
occu con inuously a e e y momen o cellula li e. The
con inuous ecycling and incessan chemical ans o ma ions,
ha encompass p ac ically all molecules, shape a c i ical scena io,
only in which cellula li e is possible (De la Fuen e, 2015).
The supe complex dynamics o igina ed by his huge
molecula u no e cons i u e he undamen al sys emic
cha ac e is ic o all basic li e uni s.
The specialis s o he li e sciences and hose o he quan i a i e
sciences, a ac ed by he biological ac , should adequa ely
unde s and he undamen al molecula dynamics o he cell, and
he su p ising magni ude ha hey each a a global le el.
Nume ous wo ks ha e been ca ied ou on molecula
ecycling, mainly o p o eins (Ma hieson e al., 2018;
Ross e al., 2020). Howe e , he s udy o ecycling o he
molecula componen s has been much less add essed. Besides,
mos o hese wo ks ha e no been ho oughly conside ed
comp ehensi ely. He e, o he i s ime, we p esen an in eg al
e iew o he molecula u no e ha includes he p o eome,
lipidome, glycome, me abolome, ansc ip ome, and main
cellula s uc u es.
All eac i e molecula ans o ma ions occu ing in he
cell a e essen ially chemical eac ions, ha is, modi ica ions
on how a oms a e bonded. P ac ically, all hese dynamics o
chemical changes in he cell a e media ed by enzymes, he mos
ex ao dina y mac omolecula nanomachines, esponsible o
b eaking and joining co alen bonds, he undamen al chemical
bonds in biological molecules. Th ough hei abili y o dec ease
he bond ac i a ion ene gy, enzymes pe manen ly modi y he way
a oms a e bonded, making possible he accele a ed c ea ion and
des uc ion o molecules. Acco dingly, enzymes a e undamen al
and essen ial molecules o me abolic li e. They a e he main
ocus o a en ion o his e iew.
Wi hou unde s anding he meaning and magni ude o he
dynamic molecula u no e ha occu s in all li ing cells, as well
as he undamen al ole o enzymes in hese pe manen me abolic
dynamics (which means ac i i ies de eloped by enzymes), i
is no possible o p ope ly unde s and wha a cell is, no he
essen ial elemen s ha unde lie in i s sel -o de ed and sel -
egula ed unc ionali y.
- Sec ion “Dissipa i e Sel -O ganiza ion o Enzyma ic
Ac i i ies, he Main Sou ce o Molecula O ganiza ion
in he Cell” add esses he dissipa i e sel -o ganiza ion
o enzyma ic ac i i ies, he main sou ce o molecula
o ganiza ion in he cell.
Enzymes a e esponsible o molecula ecycling p ocesses
shaping mul ienzyme complexes ( e e sible s uc u es o med
by se e al enzymes o a me abolic pa hway), which ca y ou
hei ac i i y wi h au onomy be ween hem playing dis inc i e
and essen ial oles in cellula physiology. When a mul ienzyme
complex ope a es a enough om equilib ium dissipa i e sel -
o ganiza ion can eme ge (Goldbe e , 2007;De la Fuen e, 2010,
2014).
He e, we show he main enzyma ic dissipa i e s uc u es:
biomolecula oscilla ions (me abolic hy hms). E en hough
sel -o ganized s uc u es a e e y di e se, and we also co e
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
o he di e en dissipa i e pa e ns including ci cadian hy hms,
bi hy hmici y, mul i-s abili y, and spa ial a eling wa es.
Nume ous physical-ma hema ical analyses o enzyma ic
pa hways ha e con ibu ed o a be e unde s anding o he
eme gence o sel -o ganized p ocesses. They a e essen ial o
esea ch he main sou ce o molecula o ganiza ion in he cell.
Mos o hese unc ional biochemical s udies ha e been ca ied
ou using sys ems o di e en ial equa ions e.g., he K ebs cycle
(Mogile skaya e al., 2006), he amino acid biosyn he ic pa hways
(Yang e al., 2005), he oxida i e phospho yla ion subsys em
(Ko zeniewski and Zoladz, 2001), he glycoly ic subsys em (Bie
e al., 1996), he ansduc ion in G-p o ein enzyme cascade
(Kass and B ay, 1996), he gene exp ession (Gonze e al., 2004),
he asco ba e-glu a hione cycle in chlo oplas s (Vale o e al.,
2016), and he cell cycle (Tyson, 1991). On he o he hand,
mo e complex analyses ha e been pe o med using non-o dina y
di e en ial equa ions, o example in he yeas glycoly ic pa hway
(De la Fuen e e al., 1995). In hese s udies, di e en a ac o
dynamics we e analyzed linked o Hop bi u ca ions (De la
Fuen e e al., 1996a), angen bi u ca ions (De la Fuen e e al.,
1996b), he classical pe iod-doubling cascade p eceding chaos
(De la Fuen e e al., 1999a), pe sis en beha io s (De la Fuen e
e al., 1998a,b, 1999b) and he mul iplici y o coexis ing a ac o s
in he phase space (De la Fuen e e al., 1998c;De la Fuen e, 1999).
The dissipa i e s uc u es ha eme ge in sel -o ganized
mul i-enzyma ic complexes cons i u e one o he mos genuine
p ope ies o cells, and he igo ous knowledge o hei na u e and
signi icance is an essen ial elemen in he comp ehension o he
biological ac a i s mos basic and elemen a y le els.
- Dissipa i e me abolic ne wo ks (DMN) and he eme gence
o he sys emic me abolic s uc u e (SMS) a e co e ed in he
“Dissipa i e Me abolic Ne wo ks and he Eme gence o he
Sys emic Me abolic S uc u e” sec ion.
Enzymes o m basic unc ional me abolic subsys ems
(mul ienzyme complexes) o u no e ac i i ies whe e
dissipa i e pa e ns eme ge. A a highe le el o complexi y,
hey shape di e en DMN, which o igina e he eme gence o he
SMS a a global le el.
To esea ch he unc ionali y o he cellula me abolism ( he
se o ac i i ies o all enzymes) a a sys emic le el, aking in o
accoun he sel -o ganized beha io , DMN was c ea ed in 1999
(De la Fuen e e al., 1999b). Essen ially, a DMN is an open
sys em o med by a gi en se o sel -o ganized mul i enzyma ic
complexes in e connec ed by biochemical subs a e luxes and
h ee classes o biomolecula egula o y signals: ac i a o y
(posi i e allos e ic modula ion), inhibi o y (nega i e allos e ic
modula ion), and all-o -no hing ype (which co espond o he
egula o y enzymes o co alen modula ion). The SMS was
obse ed o he i s ime a e pe o ming an exhaus i e
nume ical analysis wi h se e al millions o di e en DMN (De la
Fuen e e al., 1999b, 2008). Such sys emic o ganiza ion is mainly
de ined by a small se o di e en sel -o ganized mul ienzyme
complexes which a e always in ac i e s a es (me abolic co e),
while he es o dissipa i e mul ienzyme subsys ems exhibi
on-o dynamic s a es. La e , his global enzyma ic sys em was
e i ied using lux balance analysis in se e al p oka yo es and
euka yo e cells such as Saccha omyces ce e isiae,Helicobac e
pylo i, and Esche ichia coli (Almaas e al., 2004, 2005;Almaas,
2007).
Adenyla e ene gy sys em cons i u es ano he global p ocess
esponsible o he unc ional enzyma ic in eg a ion in he SMS
a a global le el. A p ima y sys emic a io be ween ATP, ADP, and
AMP concen a ions was p oposed by A kinson (A kinson and
Wal on, 1967) o calcula e he ene ge ic cellula le el, which was
denomina ed he Adenyla e Ene gy Cha ge (AEC).
Cellula ene gy quan i ica ion shows ha almos all o ganisms
keep hei AEC wi hin na ow alues unde g ow h condi ions,
mo e speci ically be ween 0.7 and 0.95, despi e he ex eme
complex luc ua ions in he adenine nucleo ide concen a ions.
Fu he quan i a i e s udies ha e shown ha each cell is
a complex non-linea ly open sys em in which he e is no a
speci ic ene gy alue ha is conse ed, bu a he dynamic
o ms o ene gy change (De la Fuen e e al., 2014). Speci ically,
in ensi e expe imen al measu emen s, which unde g ow h
cellula condi ions, ha e shown ha AEC changes be ween 0.7
and 0.95 a e in a ian ly main ained in p ac ically all classes o
cells which seems o ep esen a unc ional in eg a ion ea u e
common o all cellula o ganisms.
- The “Enzyma ic In o ma ion P ocessing, he Second
Leading Sou ce o Molecula O de in he Cell” sec ion o
his e iew deals wi h enzyma ic in o ma ion p ocessing:
he second undamen al sou ce o molecula o de in he
cell.
Enzyme ac i i y du ing molecula u no e no only o igina es
he eme gence o high sel -o ganized dissipa i e pa e ns,
s uc u ed in space and ime, bu is also capable o p oducing
complex sel - egula o y beha io by in o ma ion p ocessing
which highly inc eases he unc ional complexi y o cellula
sys em. The sophis ica ed cycles o cons uc ion and des uc ion
o he molecula componen s could no be accomplished
adequa ely wi hou his sou ce o new in o ma ion, o de ,
and o ganiza ion.
The i s quan i a i e wo k on he p ocessing o molecula
in o ma ion in bi s, in a mul i-enzyma ic complex, was
pe o med in 2012 in he yeas glycolysis (De la Fuen e and
Co és, 2012), one o he mos analyzed dissipa i e mul ienzyme
sys em, which was s udied using TE.
On he o he hand, a dynamic s uc u e o in o ma ion
p ocessing appea s in he DMN when TE is conside ed unde
sys emic ac i i y (De la Fuen e e al., 2011). Acco ding o hese
esul s, he DMN beha es as a highly complex decen alized
in o ma ion p ocessing supe -sys em ha gene a es molecula
in o ma ion lows be ween he sel -o ganized enzyma ic se s,
de ining lows o biochemical ins uc ions, a each momen ,
ha make e e y enzyma ic ac i i y o e ol e wi h a p ecise and
pa icula u no e pa e n.
Along wi h hese wo ks, di e en biological examples a e
displayed in he ex showing ha unicellula o ganisms possess
a complex sel - egula o y beha io o igina ed by biomolecula
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
in o ma ion p ocessing, he second undamen al sou ce o
o ganiza ion in he cell.
- Finally, in he “Hop ield-Type Sys emic A ac o s
in Dissipa i e Me abolic Ne wo ks. Cellula Sys emic
Beha io s” sec ion, he eme gence o Hop ield- ype
sys emic a ac o s in DMN is analyzed. I is necessa y o
unde line ha hese a ac o s allow he cellula me abolic
s uc u e (CMS) o beha e as an indi idual and comple e
in eg al sys em. As a consequence, cellula sys emic
beha io s occu .
The eme gence o Hop ield- ype dynamics was quan i a i ely
obse ed using ad anced ools o S a is ic Mechanics and
echniques o A i icial In elligence in complex enzyma ic
dynamics (De la Fuen e e al., 2013). Hop ield-like dynamics
a e cha ac e ized by mani es ing associa i e memo y (Hop ield,
1982), and he sys emic enzyma ic s udy was he i s quan i a i e
e idence ha an associa i e memo y can eme ge in an indi idual
cell. Such memo y would be a mani es a ion o eme gen
p ope ies unde lying he complex dynamics o he sys emic
cellula me abolic ne wo ks when dissipa i e enzyma ic sel -
o ganiza ion and molecula in o ma ion p ocessing ac oge he .
In con inua ion o his sys emic enzyma ic s udy (De la Fuen e
e al., 2013), and ollowing Pa lo ’s me hodological app oach
wi h dogs (Pa lo , 1927), i was obse ed ha wo di e en
unicellula o ganisms (Amoeba p o eus sp. and Me amoeba
lening adensis sp.) showed associa i e lea ning beha io s (De la
Fuen e e al., 2019a). To analyze such condi ioned beha io in
amoebae an elec ic ield was used as a condi ioned s imulus
and a speci ic chemo ac ic pep ide as an uncondi ioned s imulus.
The mig a o y ajec o ies o mo e han 700 amoebae unde
di e en expe imen al condi ions we e s udied, and he esul s
showed ha he unicellula o ganisms we e able o lea n new
sys emic beha io s, which can be conside ed as a udimen a y
o m o associa i e memo y, c ucial o go e n p ope ly cellula
mig a ion. This quan i a i e s udy demons a ed, o he i s
ime, ha associa i e memo y was also possible in unicellula
o ganisms. Such a ype o memo y could be he mani es a ion o
he eme gen p ope ies unde lying he complex dynamics o he
sys emic me abolic ne wo ks and hei Hop ield-like a ac o s.
One o he mos impo an goals o con empo a y biology
is o unde s and he undamen al p inciples and quan i a i e
laws go e ning he unc ional me abolic a chi ec u e o he
cell. In his e iew, we ha e mainly ocused on he ole o
dynamic enzyma ic p ocesses, he mechanisms implica ed in
sel -o ganiza ion (dissipa i e s uc u es), he sel - egula ion o
me abolic dynamics (molecula in o ma ion p ocessing), and
he eme gence o he cellula sys emic p ope ies (Hop ield-
like dynamics). All hese issues a e essen ial o co ec ly
unde s and wha a cell is.
To help li e scien is s who a e un amilia wi h quan i a i e
sciences unde s and hese undamen al mul idisciplina y issues,
we ha e no used ma hema ical o mula ions he e. Besides,
we ha e ein o ced he undamen al ideas wi h a conside able
numbe o biological examples.
Sys ems Biology is being inc easingly used as an app op ia e
me hodology o add ess dynamic me abolic p ocesses and he
highe -le el p ope ies eme ging in he cell om in e ac ions
be ween i s elemen a y molecula pa s, o ming complex sel -
o ganized and sel - egula ed s uc u es, om basic enzyma ic
ac i i ies o complex cellula adap i e beha io .
Sys ems biology is undamen al o unde s and he
unc ional a chi ec u e o he mos complex, sophis ica ed, and
o e whelming molecula sys em known in na u e, he li ing cell.
THE DYNAMICS ORIGINATED BY THE
MOLECULAR TURNOVER AND THE
ROLE OF THE ENZYMES IN THESE
SUPER COMPLEX DYNAMICS
Cells a e dynamic me abolic eac o s in which millions o
biochemical eac ions, igh ly in e ela ed and in eg a ed in o
sophis ica ed ne wo ks, shape he mos complex molecula
sys em in na u e.
All molecula componen s o he cell a e in a dynamic s a e
o eac i e ans o ma ions. The p o eome, lipidome, glycome,
me abolome, and ansc ip ome a e syn hesized and deg aded
con inually in all cell ypes (see Supplemen a y Ma e ial
01 o u he de ails). E en ou side he g ow h pe iod, he
in acellula mac omolecula pool is dynamic, and conside able
ene gy is expended in he con inuous p ocesses o syn hesis
and deg ada ion. Fo ins ance, only he p o ein u no e
accoun s o 38–47% o he o al ene gy p oduced in e e y cell
(Lah ee e al., 2014).
No only molecules bu also cellula s uc u es a e subjec ed
o cycles o cons uc ion and des uc ion. Fo ins ance, he
endoplasmic e iculum, he la ges endomemb ane sys em,
exhibi s a pe manen u no e ; he cy oskele on is ano he
molecula dynamic sys em ha unde goes con inuous
eo ganiza ion h ough he syn hesis and deg ada ion o i s
s uc u al elemen s du ing he cell cycle; he mi ochond ia a e
dynamic o ganelles ha a e incessan ly unde going usion,
ission, and molecula des uc ion; he pe oxisome u no e
also akes place by au ophagy- ela ed mechanism; also, cellula
memb anes a e highly eac i e dynamic s uc u es in non-s op
ecycling, so, in 30 min, an ac i e cell such as a mac ophage
ecycles by endocy osis and exocy osis an amoun o plasma
memb ane ha equals i s comple e plasma memb ane (see
Supplemen a y Ma e ial 01).
F om a molecula pe spec i e, each cell is in a pe manen
s a e o sel -cons uc ion and sel -des uc ion. This is he
undamen al sys emic cha ac e is ic o all basic uni s o li e. The
con inuous molecula ecycling ha de ines he sys emic cellula
unc ionali y elies on a supe complex dynamic sys em o med
by millions and millions o biochemical eac ions which occu
con inuously, a e e y momen o he cellula li e.
Enzymes a e he essen ial unc ional molecules o his supe
complex dynamic eac o . They a e esponsible o mos o he
molecula ans o ma ions, and such enzyma ic ac i i y, when
conside ed globally, is called cellula me abolism (S ye e al.,
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
2002). Almos all enzymes a e p o eins; howe e , some RNAs,
called ibozymes, also exhibi ca aly ic ac i i y (S ye e al.,
2002). As a piece o me abolic ac i i y, some non-enzyma ic
eac ions also occu , which a e impo an o he e olu ion o
me abolic pa hways (Kelle e al., 2015).
Almos all molecula syn hesis and des uc ion p ocesses need
o be ca alyzed so ha hey occu a adequa e as a es o sus ain
cellula li e. These ca aly ic ac i i ies in ol e he o ma ion and
b eakdown o co alen bonds, i.e., he c ea ion o des uc ion
o molecules. Enzymes a e accele a o s o biochemical eac ions.
They speed up he ca aly ic p ocesses in di e en o ms, all o
which dec ease he ac i a ion ene gy o bonds (S ye e al., 2002).
As a esul , he a es o enzyma ic p ocesses a e accele a ed om
housands o million- old, so biochemical eac ions ha would
ake yea s in he absence o ca alysis can occu in ac ions
o seconds inside he cell. Fo ins ance, a e y as ca aly ic
p ocess is p opi ia ed by o o idine 50-phospha e deca boxylase
which allows he deca boxyla ion o o o ic acid, an in e media e
in he biosyn hesis o py imidine nucleo ides, in milliseconds
unde cellula condi ions, while his eac ion akes place wi h
a hal - ime o 78 million yea s unde aw na u al condi ions
(Radzicka and Wol enden, 1995).
Me abolism can be classi ied in o wo undamen al classes:
ca abolic p ocesses ( he b eakdown o molecules ha usually
esul s in he elease o ene gy and smalle essen ial molecula
pa s) and anabolic p ocesses ( he syn hesis o molecules such
as p o eins, lipids, glycans, nucleic acids, e c., om mo e mino
molecula elemen s). These anabolic and ca abolic eac ions
ensu e molecula ecycling in he cell.
Enzymes a e he biomolecules ha pe o m he mos
impo an biological cellula unc ions. Unlike he es o he
biomolecules, enzymes a e no passi e. They a e he only
ones ha can ca y ou a ca aly ic ac i i y, ans o ming some
molecules in o o he s and de eloping complex in e ela ed
eac i e dynamics ( he enzyma ic ne wo ks, essen ial o
he unc ionali y o cell physiology). These bioca alys s a e
esponsible o he o ma ion o all he ATP in he cell, DNA
syn hesis, apop osis, mi osis, cy oskele on o ganiza ion, DNA
epai , al e na i e splicing, ch omosome egula ion, gene
exp ession, pos - ansla ional modi ica ions, Golgi appa a us
ac i i y, e c. In sho , all he main ac i i ies in he cell a e
media ed by enzymes. They cons i u e he undamen al elemen s
o all essen ial physiological p ocesses, which allow a cell o g ow,
mul iply, and adap o he ex e nal medium. Howe e , being
FIGURE 1 | Molecula in o ma ion p ocessing in yeas glycolysis. (A) The main i e e sible enzyma ic eac ions o he dissipa i e mul i enzyma ic sys em a e E1, E2,
and E3which co espond, espec i ely, o hexokinase, phospho uc okinase, and py u a e kinase. S, P1, P01, P2, P02, and P3 ep esen , espec i ely, glucose inpu
sou ce, glucose-6-phospha e, uc ose 6-phospha e, uc ose 1,6-biphospha e, phosphoenolpy u a e, and py u a e. The i s -o de a e cons an o he emo al o
glucose-6-phospha e and py u a e a e espec i ely q1and q2. The main ins abili y mechanism o dissipa ion is he complex egula ion o he phospho uc okinase
enzyme. This sel -o ganized mul ienzyme sys em exhibi s a classic quasi-pe iodic ou e o chaos unde speci ic condi ions o glucose inpu - lux (De la Fuen e e al.,
1996a). Thus, (B) he phospho uc okinase enzyme ac i i y (E2), measu ed by he uc ose 1,6-biphospha e concen a ion along he ime, shows a ansi ion
sequence wi h a s able pe iodic pa e n, quasi-pe iodic hy hms, complex quasi-pe iodic oscilla ions, and de e minis ic chaos (Ruelle-Takens-Newhouse ou e). The
panels on he igh illus a e he in o ma ion p ocessing ha egula es hese complex beha io s. Edge hicknesses a e p opo ional o he in o ma ion bi s di ided by
he maximum alue o ans e en opy, which co esponds o he ed edge. (C) No malized o al in o ma ion lows in he sel -o ganized glycoly ic sys em du ing he
quasi-pe iodic ou e o chaos. The glycoly ic sys em is sel - egula ing agains ex e nal pe u ba ions (glucose inpu s) h ough molecula in o ma ion p ocessing,
adap ing he enzyma ic pa e ns o al e a ions coming om ou side he sys em (he e, he ex e nal sou ce o glucose). Pa o his igu e has been epo ed p e iously
by De la Fuen e and Co és (2012).
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biologically essen ial, many issues o enzyme ac i i ies emain
poo ly unde s ood which wa an u he in es iga ion.
The e a e a lo o impo an biomolecules in he cell, such
as ATP, nucleo ides, lipids, s uc u al p o eins, e c., bu enzymes
cons i u e he unique ac i e biomolecules wi h he capaci y o
eo de ing he a oms, i.e., he abili y o ans o m some molecules
in o o he s c ea ing o des oying bonds be ween a oms.
Genes encode in o ma ion abou he p ima y s uc u e
o each enzyme, and his amino acid sequence de e mines
i s ca aly ic speci ici y. Howe e , he enzyma ic unc ionali y,
he se o di e en pa e ns o ac i i y ca ied ou by e e y
enzyme, canno be p edic ed om he p ima y s uc u e alone.
Enzymes a e no igid molecula s uc u es; hey ha e complex
dynamic con o ma ions and a e con inuously unde going a
wide ange o con o ma ional luc ua ions which modi y hei
ca aly ic ac i i ies. E en in he na i e s a e, an enzyme exhibi s
a ange o complex in e con e ing con o ma ions d i en by
he modynamic luc ua ions (Ramana han e al., 2014;Aga wal,
2019). Besides, he dynamic changes in he hyd a ion shell apidly
con ol hese con o ma ional luc ua ions o enzymes ( hey can
be desc ibed by an ene gy landscape) ha hinde he connec ion
be ween enzyme sequence and i s ca aly ic unc ion (Fenimo e
e al., 2004;Dunaway-Ma iano, 2008).
Besides, he ac i i ies o mos enzymes a e no cons an
in biological en i onmen s; ins ead, ca aly ic ac i i y can be
complexly egula ed hus eme ging sophis ica ed ac i i y pa e ns
(Figu e 1). These enzyma ic beha io s depend on di e en
ac o s, mainly subs a e concen a ion, and any inhibi o s o
ac i a o s. The subs a e luxes and egula o y molecula lows
o m complex dynamical ne wo ks and, as a esul , all me aboli e
concen a ions pe manen ly change wi h ime due o collec i e
in e ac ions be ween hem. The e o e, me aboli e concen a ions
a e a unc ion o sel -o ganized dynamics ha eme ge in he
enzyma ic ne wo ks (see below). Such collec i e connec i i y
in eg a ed in o biochemical ne wo ks makes highly a iable he
a e a which ca aly ic eac ions p oceed (see Figu e 2), being able
o exhibi in ini e pa e ns o ac i i y (De la Fuen e, 2014, 2015).
I should be no ed ha a g ea numbe o undamen al elemen s
o he enzyma ic ac i i y unde cellula condi ions, con inue o be
incomple e a e decades o esea ch (Ringe and Pe sko, 2009).
P ac ically all physiological p ocesses ely on he enzyma ic
ac i i y which shapes he cellula me abolism. This is an
essen ial issue o unde s and he basic p inciples o biochemical
unc ionali y a all le els o i s cellula a chi ec u e (Noble
e al., 2014). Knowing he cellula me abolism is necessa y
o unde s and he laws and p inciples ha de e mine cellula
unc ions as a whole.
Enzyma ic Sel -O ganiza ion a he
Molecula Le el
How a e enzyma ic eac ions o ganized in cells?
O e decades i was widely assumed ha enzymes we e
andomly dis ibu ed in he in acellula medium. Howe e ,
nume ous esea ches on p o ein- o-p o ein in e ac ions ha e
demons a ed ha homologous o he e ologous p o ein-p o ein
in e ac ions shape complex mac omolecula associa ions (Pang
e al., 2008). Mo e p ecisely, yeas p o eome analysis has
es ablished ha up o 83% o all p o eins cons i u e sup a-
molecula associa ions (Ga in e al., 2002), and mos o he
cellula p ocesses a e no ca ied ou by isola ed p o eins,
bu a he by mul ip o ein complexes (Ga in and Supe i-
Fu ga, 2003;Kas i is and Ga in, 2018). Such associa i e p o ein
o ganiza ion occu s in bo h euka yo e and p oka yo e cells (Ho
e al., 2002;Kühne e al., 2009).
Mul i Enzyma ic Associa ions
Di e en app oaches ha e been applied o de ec and s udy
p o ein se s, such as ad anced expe imen al molecula biology
p ocedu es, bioin o ma ics echniques, s a is ical physics ools,
and compu a ional me hods (SabziNezhad and Jalili, 2020;
Sa o i and Leible , 2020).
O all p o ein complexes, enzyme-enzyme complexes a e he
mos essen ial o biological unc ionali y. The basic concep o
mul ienzyme associa ions was ini ially sugges ed by A. M. Kuzin
in he se en ies o he las cen u y (Kuzin, 1970). Besides, Paul
A. S e e was he i s o obse e a non- i ial sup amolecula
enzyma ic o ganiza ion in he ci ic acid cycle (S e e, 1972), who
la e called “me abolon” o all hese ypes o mul ienzyme se s
ha can ca alyze wo o mo e sequences o a me abolic ou e
(S e e, 1985, 1987).
The mul ienzyme complex is a unc ional e e sible
supe s uc u e o med by se e al enzymes o a me abolic
pa hway ha uses non-co alen in e ac ions such as hyd ogen
bonding, ca ion-pi in e ac ion, and hyd ophobic o ce o
main ain ensemble se e al ca aly ic elemen s (Figu e 1). Such
enzyma ic complexes allow highly selec i e eac ions, inc easing
hei ca aly ic e iciency (Con ado e al., 2008;A aiza-Oli e a
e al., 2013).
Many enzymes belonging o me abolic pa hways ha shape
hese complex sup amolecula s uc u es ha e been s udied, o
ins ance, yp ophan syn hase complex (Hila io e al., 2016), a y
acid syn hase (Maie e al., 2006), glycolysis (Kohnho s e al.,
2017), Cal in cycle (Gon e o e al., 2018), cellulosome (Dou
e al., 2015), py imidine biosyn hesis (Se e e al., 1998), pu ine
biosyn hesis (Hoskins e al., 2004), syn hesis o 50-phosphosul a e
(Sun and Leyh, 2006), aldolase dehyd ogenase complex (Ca e e
e al., 2011), polyke ide syn hases (Tsai and Ames, 2009),
p o easome (Jung and G une, 2012), py u a e dehyd ogenase
(Iza d e al., 1999), ca bamoyl phospha e syn he ase (Thoden
e al., 1997), alpha-ke oglu a a e dehyd ogenase (T e e and
Adam-Vizi, 2005), u ea cycle (Wa o d, 1989), and aldehyde–
alcohol dehyd ogenase (Kim e al., 2020).
A mul ienzyme complex p o ides e icien ad an ages o e
indi idual enzymes. In many obse a ions, mul ienzyme se s can
ans e he me aboli es om one enzyme o he ac i e si e o he
nex consecu i e enzyme wi hou di usion in o he bulk medium,
a oiding hei e en ual loss (subs a e channeling). The ime o
di usion be ween successi e ca aly ic s eps is minimized. This
non-co alen di ec ans e p ocess o me abolic in e media es
o igina es as e ca alysis, making he ca alysis mo e e icien in
he mul ienzyme se s (O ádi and S e e, 2000;O ádi and Saks,
2004;Cas ellana e al., 2014). Subs a e channeling may occu in
se e al ways i.e., ac oss enzyme channels o o e he elec os a ic
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
FIGURE 2 | Dynamic ca aly ic pa e ns eme ge in a dissipa i e me abolic ne wo k. A sel -o ganized me abolic ne wo k shaped by 18 dissipa i e mul ienzyme
complexes, in e connec ed by di e en subs a e luxes, was subjec ed o wo ex e nal condi ions: (A) wo inpu s o subs a e sou ces S1–S2, and (B) one inpu o
ex e nal subs a e sou ce S1, in he igh panel. As a esul o he ne wo k ac i i y, he mul ienzyme complex MSb12 was pe manen ly ac i e unde bo h ex e nal
condi ions (me abolic co e), MSb15 was inac i e unde he wo inpu s o subs a e sou ces S1–S2, whe eas i was in e mi en ly ac i e unde one ex e nal s imulus.
O he dissipa i e mul ienzyme se s exhibi ed on-o changing ac i i y s a es. The dissipa i e ne wo k is an open sys em and MSb6 ac i i y ends ou side he
me abolic ne wo k. In he ne wo k, hese sel -o ganized mul ienzyme complexes au onomously exhibi many enzyma ic ansi ions (mo e han 350) be ween di e en
spon aneous pe iodic oscilla ions and s eady-s a es when hey a e ac i e. Thus, wo examples o MSb12 ca aly ic ac i i ies a e p esen ed in panel (C), unde wo
sou ces o ex e nal subs a es S1-S2, and in (D) unde one s imulus S1. Di e en changes in he ampli ude o he dissipa i e ca aly ic ac i i ies o he mul i enzyma ic
se s can be obse ed in panel (E,F), which show he complex enzyma ic pa e ns ha eme ge in he dissipa i e me abolic ne wo k unde hese cellula condi ions.
Pa o his igu e has been epo ed p e iously by De la Fuen e e al. (2011).
su ace o he p o ein supe s uc u e (Swee lo e and Fe nie, 2018;
S ed uži´
c e al., 2020;Zhang and Fe nie, 2020).
Also, in acellula memb anes and s uc u al p o eins
may e e sibly in e ac wi h enzyma ic se s o igina ing
mic ocompa men s, which ep esen ano he ad an age
o mul ienzyme complexes (Saks e al., 2007, 2009;Monge
e al., 2009). Thus, i has been obse ed in many cases
ha enzymes ac i i y is p oduced in hese small specialized
mic oen i onmen s, limi ed ei he by su ace o es ic ed by
olume, which is mo e s able agains he biochemical changes
in he in acellula medium, allowing mo e e icien ca aly ic
eac ions (A aiza-Oli e a e al., 2013;Küken e al., 2018).
O he pieces o e idence ha e shown ha some me abolic
compa men s a e liquid-like, which a e o med by phase
sepa a ion om he cy oplasm. Such liquid-like compa men s
desc ibe non-memb ane-bound es ic ed spaces as phase-
sepa a ed, also c ea ing small specialized mic oen i onmen s
(Hyman e al., 2014).
In he global molecula c owding ha cons i u es he cell,
enzymes a ely unc ion in isola ion, bu a he as componen s
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
o ca aly ic se s and in e dependen coupled biop ocesses
(G eco and C is ea, 2016).
DISSIPATIVE SELF-ORGANIZATION OF
ENZYMATIC ACTIVITIES, THE MAIN
SOURCE OF MOLECULAR
ORGANIZATION IN THE CELL
Cells a e open dynamic me abolic eac o s ha exchange
ma e and ene gy wi h he ex e nal en i onmen , ob aining
undamen al elemen s o su i al om he nu ien s h ough
mul i-enzyma ic eac ions. All li ing o ganisms exhibi highly
o de ed enzyma ic dynamic p ocesses and use he ene gy
o nu ien s o main ain non-equilib ium s a es, whe e
sophis ica ed s uc u es, complex biochemical pa e ns, and
collec i e biomolecula sel -o ganiza ion eme ge. When any cell
eaches equilib ium wi h he ex e nal medium, i s cha ac e is ic
high unc ional and molecula o de disappea s and i dies.
The modynamics is a necessa y ield o scien i ic knowledge
o p ope ly unde s and some essen ial p inciples o biochemical
p ocesses ( on S ocka , 2010;Kondepudi and P igogine, 2014).
So, en opy is an impo an concep ha allows quan i ica ion
o unce ain y and diso ganiza ion in a sys em. In isola ed
sys ems, en opy ne e dec eases. Con e sely, i inc eases owa d
a maximum a equilib ium. In open sys ems, which exchange
ene gy and ma e wi h hei en i onmen , en opy can be
sus ained o dec ease, a oiding a s a e o he modynamic
equilib ium. The nega i e a ia ion (p oducing a consequen
inc ease in he en opy o he su oundings) co esponds o
a ela i e o de inside he sys em. This is possible by he
dissipa ion o ene gy i.e., he ene gy becomes no only una ailable
bu i eco e ably los in he su oundings h ough i e e sible
p ocesses (Niebel e al., 2019). The endency o an open sys em
ha consumes ene gy wi h low en opy o dissipa e ene gy wi h
highe en opy o i s su oundings ( hus, he sys em succeeds in
libe a ing i sel o pa o i s own p oduced en opy) can allow
sel -o ganiza ion o he sys em (Ebeling and Ulb ich , 1986).
This p inciple is undamen al o unde s and he main sou ce o
molecula o de in he cell.
The heo e ical basis o sel -o ganiza ion was o mula ed in
1977 by he Nobel P ize Lau ea e in Chemis y Ilya P igogine in
his wo k on dissipa i e s uc u es (Nicolis and P igogine, 1977).
Speci ically, dissipa i e sel -o ganiza ion a he molecula le el
cons i u es spon aneous highly o de ed mic oscopic s uc u es
a om he modynamic equilib ium which a e cha ac e ized by
cohe en spa ial and/o empo al pa e ns. Due o complex non-
linea in e ac ions among molecula componen s and d i en
by ene gy dissipa ion, hese sel -o ganized s uc u es eme ge
inc easing he s uc u al and unc ional complexi y o he sys em.
Such eme gen sel -o ganized dynamic s uc u es in space and
ime a e called sel -o ganized dissipa i e s uc u es (Nicolis and
P igogine, 1977;Kondepudi and P igogine, 2014).
Dissipa i e sel -o ganized p ocesses use he ene gy in low
o gene a e a nega i e en opy a ia ion in he open sys em
which co esponds o an eme gen posi i e inc emen in he
in o ma ion sel -con ained in he sys em. Such in o ma ion
inc eases he complexi y, being able o p oduce highly-o de ed
mac os uc u es and complex unc ional dynamic beha io s.
Non-linea in e ac ions and i e e sible p ocesses may ampli y
luc ua ions leading o a dynamic s a e, a om he equilib ium,
in which he sys em becomes spa ially and empo ally sel -
o ganized (Klimon o ich, 1999;Halley and Winkle , 2008;
Mis eli, 2009)
One o he mos signi ican scien i ic disco e ies o he
20 h cen u y conce ns his new sou ce o molecula o de
in na u e, he dissipa i e sel -o ganiza ion. Such a sou ce is
c i ical o unde s and he dynamic ac i i ies o mul ienzyme
complexes and he sys emic unc ional o ganiza ion in he
cell. The wo k o Ilya P igogine ep esen s a p o ound and
o iginal ea men o molecula o ganiza ion in na u e, wi h
deep implica ions o unde s anding biological li e a i s mos
undamen al le els.
Dissipa i e Sel -O ganiza ion o
Mul ienzyme Complexes
How does he unc ionali y o mul ienzyme complexes in he
p e ailing condi ions inside he cell wo k?
I is well es ablished ha enzymes, in addi ion o o m
mul ica aly ic se s, can shape dissipa i e s uc u es in which
wo undamen al ypes o dynamic sel -o ganiza ion can eme ge:
empo al hy hms and spa ial wa es.
When a mul ienzyme se ope a es a enough om
equilib ium and dissipa i e sel -o ganiza ion eme ges, all
he enzymes o he complex do unc ion as a whole, showing
eac i e coo dina ion be ween hem (long- ange cohe ence) in
such a way ha all he subs a e and p oduc concen a ions
spon aneously s a o oscilla e along ime ( empo al hy hms),
see Figu e 1. As a consequence, housands and housands
o molecules and ions ha shape he mul ica aly ic sys em
(subs a es, p oduc s, p o ons, egula o y molecules, and o he
me aboli es) expe imen massi e oscilla o y eo ganiza ions
in hei molecula concen a ions. Such dynamics a e
mainly cha ac e ized by collec i e synch onized beha io s,
unc ional co ela ions be ween molecula componen s
sepa a ed by mac oscopic dis ances, cohe en pa e ns,
and highly coo dina ed in eg a i e p ocesses (De la Fuen e,
2010). Dissipa i e sel -o ganized ca aly ic beha io s ind hei
oo s in he non-linea enzyma ic p ocesses which mainly
in ol e allos e ic egula ion, au oca alysis, coope a i i y,
and eed-back in e ac ions (Goldbe e , 2002, 2007, 2018;
De la Fuen e, 2014).
All me aboli e concen a ions o mul ienzyme se s ha
exhibi dissipa i e sel -o ganiza ion p ocesses p esen ansi ions
be ween complex oscilla ions and quasi-s eady s a es unde
cellula condi ions (De la Fuen e, 2015). The quan i ica ion
o ce ain in acellula molecules h ough nano biosenso s in
li ing cells has shown complex quasi-s eady s a es and oscilla o y
pa e ns whose dynamics a e ne e cons an (Ozalp e al., 2010).
Di e en expe imen al pieces o e idence sugges ha oscilla o y
beha io s a e much mo e equen han quasi-s eady s a es in
cellula condi ions (Lloyd and Mu ay, 2005, 2006).
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Biomolecula oscilla ions a e a genuine beha io o he
complex sel -o ganized enzyma ic p ocesses in basic uni s
o li e. Such oscilla o y beha io spon aneously occu s a
om he modynamic equilib ium, when he sys em is o med
by i e e sible enzyma ic p ocesses wi h non-linea kine ics,
Figu e 1. In acellula molecula oscilla ions we e epo ed
in: ATP, ADP, and AMP nucleo ides (De la Fuen e e al.,
2014), mic o ubule polyme iza ion (Lange e al., 1988) and
o he cy oskele al s uc u es (K use and Jüliche , 2005), cyclins
(Hunge buehle e al., 2007), cyclic AMP concen a ion (Holz
e al., 2008), cy okinins (Ha ig and Beck, 2005), ee a y
acids syn hesis (Ge y-Kaushik e al., 2005), ac in polyme iza ion
(Rengan and Omann, 1999;Neg e e e al., 2016), biosyn hesis o
phospholipids (Má quez e al., 2004), u ea cycle (Fuen es e al.,
1994), p o eolysis (Kindzelskii e al., 1998), glycolysis (Dano
e al., 1999), me abolism o ca bohyd a es (Jules e al., 2005),
in acellula glu a hione concen a ion (Lloyd and Mu ay,
2005), K ebs cycle (Wi mann e al., 2005), mi ochond ial
me abolic p ocesses (Aon e al., 2008), pho osyn he ic eac ions
(Sm cino á e al., 1998), CO2(Tyson, 2002), p o ein kinase
ac i i ies (Chiam and Rajagopal, 2007), ansc ip ion ac o s
(Ga mendia-To es e al., 2007), espi a o y me abolism (Lloyd
e al., 2002), in acellula calcium concen a ion (Ishii e al.,
2006), pe oxidase-oxidase eac ions (Mølle e al., 1998),
memb ane ecep o ac i i ies (Placan onakis and Welsh, 2001),
memb ane lipid oscilla ion (Nakamu a, 2018), ERK/MAPK
me abolism (Shanka an e al., 2009), in acellula pH (Sánchez-
A máss e al., 2006), in acellula ee amino acid pools (Hans
e al., 2003), memb ane po en ial (De Fo es and Wheele , 1999),
me abolism o mRNA (Kle ecz and Mu ay, 2001), min-p o eins
(We mann and Ka s en, 2018), be a-oxida ion o a y acids
(Ge y e al., 2000), amino acid anspo s (Ba il and Po e ,
1968), insulin sec e ion (Tyson, 2002), e c.
Mo eo e , a me abolic o ches a ion has been obse ed in cells
a a sys emic le el, by which he en i e me abolome and mos
o he ansc ip ome oscilla e (Kle ecz e al., 2004;Lloyd and
Mu ay, 2006;Mu ay e al., 2007). Mo e speci ically, se e al
s udies ha e analyzed oscilla o y p ocesses in he ansc ip ome
(Tonozuka e al., 2001;Tian e al., 2005;Chabo e al., 2007).
These s udies ha e shown ha a leas 60% o all ansc ip ions
oscilla e wi h an app oxima e pe iod o 300 min (Tu e al., 2008).
Mic oa ay analysis om S. ce e isiae in con inuous synch onous
cul u e shows a genome-wide oscilla ion in ansc ip ion
p ocesses coupled o espi a ion wi h maxima o ansc ip le els
a in e als o abou 40 min (Kle ecz e al., 2004).
The oscilla o y pe iods o me abolic hy hms ange om
milliseconds o minu es and hou s (Chance e al., 1973;Be idge
and Galione, 1988;Aon e al., 2006;B odsky, 2006;Roussel e al.,
2006). Complex pe iodic oscilla ions, including bu s ing hy hms
and de e minis ic chao ic phenomena, ha e o en been de ec ed
(Olsen and Degn, 1985;Dekhuijzen and Bagus , 1996;Almei a
and Gusman, 2017;Hel be g e al., 2019).
Dissipa i e s uc u es a e e y di e se (Goldbe e , 2018).
Fo ins ance, besides hy hmic me abolic beha io s, he
coexis ence be ween wo s able oscilla ions in a biochemical
se (bi hy hmici y) and he coexis ence o se e al s able s eady
s a es (mul is abili y) may also eme ge in he same molecula
sys em. Mul is abili y has been obse ed in di e en biosys ems
such as he calcium/calmodulin-dependen p o ein kinase II
(Zhabo insky, 2000), NF-κB signaling (Pêkalski e al., 2013),
apop osis (Ben ele e al., 2004), cy oskele on con ol (By ne
e al., 2016), lac ope on (San illán and Mackey, 2008), and
signal ansduc ion (Xiong and Fe ell, 2003). The coexis ence
be ween wo oscilla o y egimes and a s eady-s a e wi h pe iodic
beha io (ha d exci a ion) has also been obse ed in nume ical
s udies o mul ienzyme complexes (De la Fuen e e al., 1998c;
De la Fuen e, 1999) and chemical sys ems (Gu man e al., 1980).
Ano he class o sel -o ganized biological dissipa i e p ocesses
is ci cadian hy hms, which exhibi an oscilla o y pe iod close o
24 h (da k–ligh cycle du ing he Ea h’s o a ion pe iod). These
endogenous au onomous oscilla o s can adap hei in e nal
me abolism o changes in he ex e nal en i onmen (ligh ,
empe a u e, ood a ailabili y, e c.) du ing 24-h day/nigh cycles
(Yanling e al., 2019). Ci cadian hy hms exis in all ypes
o cells om p oka yo es o euka yo es, and hese dissipa i e
pa e ns egula e a g ea a ie y o impo an physiological
p ocesses (Wijnen and Young, 2006). Fo ins ance, oscilla ing
genes a e also usually ci cadian (Tu le e al., 2005). E en, i has
been obse ed in some cells ha 80–90% o he ansc ip ome
show a hy hmic gene exp ession wi h cycles o 24–26 h
(Conno and G acey, 2011).
Ci cadian ansc ip ion- ansla ion cycles a e in e wined
wi h di e en me abolic ac i i ies and espi a o y oscilla ions,
which ensu es he sys ema ic coo dina ion and in eg a ion o
cellula physiological p ocesses (Caus on, 2020).
Las ly, a undamen al ype o dissipa i e s uc u e in cells is
he spa ial a eling wa es which consis o h ee-dimensional
sel -o ganized cohe en oscilla ion o me aboli e concen a ions
ha p opaga es p og essi ely ac oss he in acellula medium,
eminiscen o a wa e mo ing ac oss wa e . These wa e pulses
o biochemical ac i i y, mo ing h ough subcellula domains
o e la ge in acellula dis ances, a e oo as (5–30 µm s−1
o calcium wa es; Ja e, 2002) and ep esen an essen ial
mechanism o long- ange unc ional in e connec ion in he cell.
Spa ial a eling wa es ha e a c ucial ole in coo dina ion and
synch oniza ion among di e en me abolic p ocesses, and hese
dissipa i e pa e ns exhibi o he cha ac e is ics in hei shape o
oscilla ion, cellula loca ion, and molecula composi ion (Gu h ie
e al., 1999;Scemes and Giaume, 2006;Ca s en and Ka s en,
2017). Some examples o spa ial biochemical oscilla ions ha e
been obse ed in calcium ions (Ja e, 2008), ac in dynamics
du ing cell locomo ion (Vicke , 2002;Alla d and Mogilne ,
2013), apop o ic signals (Cheng and Fe ell, 2018), mi ochond ial
edox (Romashko e al., 1998), NAD(P)H (Kindzelskii and Pe y,
2002;Slaby and Lebiedz, 2009), sodium ions wa es in as ocy es
(Be na dinelli e al., 2004), phosphop o ein wa es (Ma ke ich
e al., 2006), Cdk1 wa es implica ed in he cell cycle (Deneke e al.,
2016), mi o ic wa es (Nole e al., 2020), adenosine iphospha e
(Ueda e al., 1990; Newman, 2001), NAD(P)H and p o ons (Pe y
e al., 2000), phospha idylinosi ol (3,4,5)- isphospha e (Asano
e al., 2008), ROS molecules (Zhou e al., 2010), and mi ochond ia
ac i i y (Ku z e al., 2010).
Each cell is a supe dynamic me abolic sys em in which sel -
cons uc ion and sel -des uc ion o molecules occu ollowing
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FIGURE 6 | Equi alen Hop ield ne wo k h ough a Bol zmann machine in dissipa i e me abolic ne wo ks. In bo h condi ions analyzed: (A) only an ex e nal sou ce o
biochemical subs a e S1, (B) wo ex e nal inpu s o subs a e sou ces S1 and S2, he weigh s, depic ed in ed, and he h esholds, plo ed in blue, show a s ongly
non-Gaussian dis ibu ion. (C,D) Two ma ices o weigh s connec i i y ob ained unde wo ex e nal condi ions a e p esen ed; hey we e lea ned om he dissipa ed
me abolic ne wo k (Figu e 2) by he Bol zmann machine. Pa o his igu e has been epo ed p e iously by De la Fuen e e al. (2013).
Thi d, “ he sys emic a ac o s ha eme ge in he sys em
co espond o Hop ield-like dynamics which can s o e me abolic
in o ma ion pa e ns (Hop ield, 1982). The biochemical
in o ma ion con ained in he a ac o s beha es as a unc ional
me abolic memo y, i.e., enzyma ic ac i i y pa e ns s o ed as
s able s a es, egula es bo h he pe manen ca aly ic changes in
he sys emic ne wo k and he me abolic esponses o igina ed
o in eg a e he pe u ba ions coming om he ex e nal
en i onmen p ope ly. When an ex e nal s imulus pa e n
is p esen ed o he sys em, he ne wo k s a es a e d i en
by he in insic enzyma ic dynamics owa d a de e mined
sys emic a ac o which co esponds o a se o memo ized
biochemical pa e ns” (De la Fuen e, 2015). As i is gene ally
known, such “pa e n-comple ion” dynamics ha e long been
s udied in Hop ield ne wo ks, and hey a e usually e e ed o as
“associa i e memo y” (Hop ield, 1982;He z e al., 1991;Ami ,
1992;Pe e o, 1992).
In so , Hop ield-like me abolic a ac o s s o e sys emic
enzyma ic dynamics which may be p ope ly eco e ed
om ex e nal s imuli. Me abolic dynamics a e sys emically
go e ned by hese me abolic a ac o s which modula e
he enzyma ic ac i i ies, change he connec ions among
dissipa i e mul ienzyme associa ions, and s ably s o e hese
dynamic connec ions.
The s udy wi h Hop ield ne wo ks (De la Fuen e e al.,
2013) quan i a i ely e idenced, o he i s ime, he possibili y
ha a cell can ha e associa i e memo y. Such Hop ield-
like memo y would be a cellula ype o epigene ic memo y
(De la Fuen e, 2015).
Ve i ica ion o Associa i e Memo y in
Unicellula O ganisms
The p inciples o associa i e memo y we e disco e ed a he
beginning o he 20 h cen u y by Nobel Lau ea e I an Pa lo in
his classic s udies wi h dogs, which opened up a new pa adigm in
beha io al sciences.
In all o ganisms wi h a ne ous sys em, associa i e lea ning
and memo y a e essen ial cogni i e cha ac e is ics ha allow
ob aining c i ical in o ma ion o adap a ion and su i al,
mas e ing new beha io s h ough he associa ion o di e se
s imuli. These cha ac e is ics a e ubiqui ous in nume ous species
om mollusks o humans, bu un il now hey ha e ne e been
obse ed in indi idual cells.
To expe imen ally e i y he eme gence o associa i e memo y
in cells, he sys emic mo ili y pa e ns o wo euka yo ic
mic oo ganisms such as A. p o eus and M. lening adensis
we e analyzed unde an associa i e condi ioning se ing (De la
Fuen e e al., 2019a). Fo his pu pose, wo s imuli we e es ed
ollowing Pa lo ’s concep o expe imen s, a sui able di ec -
cu en (DC) elec ic ield, and an N- o myla ed ipep ide linked
o amoeba nu i ion.
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
FIGURE 7 | Me abolic associa i e memo ies in dissipa i e me abolic ne wo ks. (A,B) One me abolic memo y encoded in he weigh s. In black a e depic ed some
dissipa i e me abolic dynamics when he ini ial ac i i y is he same as he dynamic memo y gi en by he LSE solu ion (Leas Squa e E o ); his biochemical dynamic
memo y is a local minimum o he equi alen Hop ield ne wo k ob ained om he dissipa i e ne wo k (Figu e 2), a p oo o associa i e memo y. An a bi a y solu ion
is also shown in ed which is o poo e quali y han he ob ained by LSE. (C–F) In black, wo me abolic memo ies encoded in he weigh s unde only ex e nal inpu
sou ce o subs a e S1 and bo h ex e nal inpu s o subs a e sou ces S1 and S2 a e plo ed. The i s me abolic memo y is shown in panels (C,E), and he second
me abolic memo y is displayed in panels (D–F). Bo h wo me abolic memo ies a e local minima, which does no occu wi h an a bi a y solu ion plo ed in ed. Thus,
he equi alen Hop ield ne wo k o he dissipa i e me abolic sys em can exhibi associa i e memo y. Times a e in Mon e Ca lo S eps’ uni s (MCS). Fluc ua ions we e
es ablished by a empe a u e pa ame e o T= 0.7. The sys emic enzyma ic ac i i ies o he Dissipa i e Me abolic Ne wo k (Figu e 2) a e d i en by Hop ield-like
a ac o s wi h a capaci y o s o e ca aly ic beha io s which can be e ie ed app op ia ely om de e mining ex e nal inpu s o subs a e sou ces. These sys emic
a ac o s go e n he me abolic ac i i ies, change he unc ional connec i i y be ween he dissipa i e sel -o ganized mul ienzyme se s, and s ably keep hese
changes. Pa o his igu e has been epo ed p e iously by De la Fuen e e al. (2013).
The mos impo an aspec s o his wo k on cellula associa i e
condi ioning a e summa ized below:
- Fi s , i was ound ha in he absence o s imuli cellula
locomo ion di ec ionali y displayed a andom dis ibu ion
when amoebae and me amoebae p obed almos all he
di ec ions o he expe imen al chambe (Figu e 8A).
- In he nex expe imen al s ep, gal ano axis, amoebae,
and me amoebae exhibi ed an unambiguous sys emic
eac ion consis ing o mo emen o he nega i e pole when
subjec ed o a s ong DC elec ic ield o abou 300–
600 mV/mm (Figu e 8B).
- In he hi d s ep, he esponse o bo h unicellula o ganisms
was s udied du ing hei exposu e o a g adien o nFMLP,
dis ibu ed in he le pa o he expe imen al chambe
(chemo axis, Figu e 8C). In hese ci cums ances, mos cells
showed a s ochas ic mig a ion wi h obus di ec ionali y
owa d he pep ide.
- In he ou h s ep, an induc ion p ocess was pe o med. To
his end, bo h s imuli, gal ano ac ic and chemo ac ic, we e
applied o amoebae simul aneously o 30 min. The nFMLP
pep ide solu ion was added o he anode well, on he le
pa o he chambe (Figu e 8D). In hese expe imen s, only
abou hal o he amoebae and me amoebae mig a ed o he
ca hode and he es mo ed o he anode si e, whe e he
pep ide was deposi ed.
- Finally, o check i he cells conse e hei mo emen
pa e n o he anode-nFMLP, he cells ha showed such
mig a ion in he ou h s ep we e exposed once mo e o
30 min o a single elec ic ield s imulus, omi ing pep ide
a he anode. The indi idual cell ajec o ies analyzed a e
he expe imen s e ealed he mig a ion o mos o hese
cells o he anode in he absence o pep ide (Figu e 9),
so i was shown ha a e he induc ion p ocess, amoebae
and me amoebae de eloped a new pa e n o locomo ion:
mo ing o he anode unde gal ano axis condi ions. I is
wo h emembe ing ha almos all cells in he DC ield
mo e o he ca hode (see Figu e 8B).
Unde he applica ion o wo simul aneous s imuli (induc ion
p ocess), he DC elec ic ield and he pep ide ela ed o he
nu i ion o amoeba, placed a he posi i e pole, some amoebae
seem o ela e hese s imuli (anode and pep ide), and subsequen
con ol es s showed ha mos o he condi ioned A. p o eus
and M. lening adensis changed hei sys emic beha io , mo ing
owa d he anode whe e he e was no nFMLP pep ide.
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
FIGURE 8 | Mig a ion ajec o ies o Amoebae p o eus unde ou basic and independen expe imen al condi ions. (A) In he absence o s imuli, amoebae showed
andom mo ion in all di ec ions om he cen al poin whe e hey we e placed. (B) In he DC elec ic ield, all cells mo ed o he nega i e pole (gal ano axis). (C) In
he chemo axis assay, 86% o he amoebae exhibi ed obus di ec ionali y owa d he pep ide loca ion. (D) In he induc ion p ocess (simul aneous gal ano axis and
chemo axis), 53% o cells mig a ed owa d he anode-pep ide. “N” numbe o cells es ed, “ ” du a ion o he expe imen . “p” nFML chemo ac ic ipep ide, “+”
anode, “-” ca hode. In panels (A–D), he dis ance in bo h axes is in mm. The ini ial loca ion o each cell was a he cen e o he diag am. Pa o his igu e has been
epo ed p e iously by De la Fuen e e al. (2019a).
They acqui ed a new pe sis en pa e n o cellula mo ion,
desc ibed by he mo e owa d he anode (Figu e 9), ins ead
o hei es ablished p opensi y o un o he ca hode. The
condi ioned amoebae we e able o associa e simul aneous bu
un ela ed pas e en s, p oducing pe sis en mo emen (con a y
o hei na u al endency), which on a e age could con inue o
44 min. Besides, a as numbe o s ic con ols p o ed he
obus ness and p edic abili y o his beha io .
These expe imen s, in which a single cell links wo di e en
simul aneous s imuli hus de eloping a new beha io , a e he i s
published e idence ha an associa i e Pa lo ian-like memo y is
p esen in single cells (De la Fuen e e al., 2019a).
Cellula condi ioning may be necessa y o c i ical
unc ions, o example, he egula ion o mig a ion.
Locomo ion mo emen s a e undamen al no only o
su i e and a oid p eda o s, bu also in indi idual cells o
mul icellula o ganisms o ca y ou essen ial li e p ocesses
like emb yogenesis, o ganogenesis, immune esponse, issue
epai , and o he s. Se e al se e e heal h condi ions, such as
cance , ascula and hea diseases, and in ellec ual disabili y,
may de elop as he consequences o inaccu a e con ol o
his sys emic mo ili y p ope y. Such mig a o y cellula
abili ies a e also p esen in he me as a ic p ocess o cance
(De la Fuen e and López, 2020).
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
FIGURE 9 | Expe imen al e idence o associa i e memo y in cells. In he gal ano axis, almos all cells o wo species gene ally mo e o he ca hode. A e he
condi ioning p ocess (simul aneous applica ion o bo h gal ano ac ic and chemo ac ic s imuli), he cells, which showed mig a ion o he anode, we e es ed in
ano he gal ano axis; mos o hem pe sis ed in mo ion owa d he anode in he absence o pep ide. Thus, hese cells e ealed he unknown abili y o acqui e a new
beha io and memo ize i o an a e age o 40 min, a ela i ely long ime compa ed o hei li e cycle. Pa o his igu e has been epo ed p e iously by De la Fuen e
e al. (2019a).
INTEGRATIVE SUMMARY
In his e iew, we ha e mainly app oached ou aspec s
ha cha ac e ize cellula unc ioning: he ole o dynamic
molecula p ocesses, he mechanisms implica ed in sel -
o ganiza ion (dissipa i e s uc u es) and he sel - egula ion o
me abolic dynamics (molecula in o ma ion p ocessing), and he
eme gence o he cellula sys emic p ope ies.
Mo e speci ically, he wo k ocuses on he main p inciples ha
go e n enzyma ic ac i i y, unde complex dynamic condi ions
p e ailing inside he cell, which a e c ucial o elucida e he
s uc u al and unc ional a chi ec u e o basic uni s o li e.
The scope o Sys ems Biology applied he e is based
on in eg a ing concep s and knowledge in Biochemis y,
Enzymology, Molecula and Cell Biology, and o he biological
sciences. We also discussed he esul s o quan i a i e esea ch,
analyzed by applica ion o physical-ma hema ical ools such as
s a is ical mechanics, di e en ial calculus, disc e e ma hema ics,
a i icial in elligence, compu ing, and o he s. Ne e heless,
a o ing he didac ic pu pose o he e iew we did no use he
ma hema ical o mula ions.
The ollowing pa ag aphs add some conclusi e examples and
summa ize he main aspec s o his e iew in an in eg a i e way.
Cellula Molecula Dynamics
S ic ly speaking om a biochemical iewpoin , he cell is
a complex molecula eac o , ex emely sel -o ganized in a
sophis ica ed manne , and in a pe manen biomolecula ecycling
s a us (sec ion “The Dynamics O igina ed by he Molecula
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
Tu no e and he Role o he Enzymes in These Supe
Complex Dynamics”).
Millions o biochemical eac ions happen simul aneously in
e e y basic uni o li e a any ime. This p ocess o eac i e
ans o ma ions also includes subcellula s uc u es. No hing is
ine , all he molecules and s uc u es ha make up each cell
unde go complex chemical ans o ma ions (see Supplemen a y
Ma e ial 01). No ice ha , despi e he e o s, many aspec s
o cellula ecycling emain poo ly unde s ood by molecula
expe imen alis s.
The cell is an ex emely complex and dynamic sys em; he
endless molecula u no e , which cha ac e izes i , modi ies he
chemical composi ion o he whole eac o e e y second and, as a
consequence, he concen a ion pa e ns o ions and molecules
change pe manen ly o e ime. These con inuous cycles o
syn hesis and des uc ion, and incessan chemical molecula
ans o ma ions shape he essen ial scena io in which cellula li e
is possible. When his dynamic p ocess o molecula u no e
collapses, he cell dies. This is he main sys emic cha ac e is ic
o all li ing unicellula o ganisms.
The consequences o sel - egula ed u no e dynamics a e
adequa e cellula g ow h, he de elopmen o all physiological
p ocesses o main ain i s unc ional s uc u es, con inuous
adap a ion o he en i onmen , and mi osis.
The highly complex o ganiza ion o cellula u no e
dynamics de ies he human in ellec . Any a emp o syn he ically
ep oduce his global molecula u no e , ei he in i o o
in silico, has ailed so a . In e e y cell, molecula syn hesis and
des uc ion a e compensa ed and ha monized be ween hem,
ollowing complex and un epea able eac i e pa e ns, whose
laws and de ining p inciples a e s ill unknown.
Enzymes, Essen ial Cellula Molecules
Enzymes a e undamen al molecules o me abolic li e. Molecula
eac i e ans o ma ions a e essen ially chemical eac ions,
modi ica ions on how a oms a e bonded. P ac ically, all
eac i e ans o ma ions in he cell a e media ed by enzymes,
ex ao dina y mac omolecula nanomachines esponsible o
b eaking and joining co alen bonds, he undamen al chemical
links in biological molecules (sec ion “The Dynamics O igina ed
by he Molecula Tu no e and he Role o he Enzymes in These
Supe Complex Dynamics”). Cellula li e would be impossible
wi hou enzymes; hey a e key p o agonis s in all eac i e and
physiological p ocesses in he cell.
Unlike o he cellula molecules, enzymes a e ac i e
mac omolecules esponsible o he chemical wo k. Th ough
hei abili y o dec ease he ac i a ion ene gy o bonds, enzymes
pe manen ly modi y how a oms a e bonded, making possible he
accele a ed c ea ion and des uc ion o molecules.
Ca aly ic enzyma ic ac i i ies a e e med me abolic p ocesses.
The e a e wo basic ypes o enzyma ic eac ions, ca abolism
(implica ed in molecule des uc ion) and anabolism (implica ed
in molecule syn hesis). Toge he , hese enzyma ic ac i i ies a e
called cellula me abolism. In sho , he cell is a complex
enzyme-media ed me abolic sys em whe e eac i e molecula
ans o ma ions o syn hesis and des uc ion happen unceasingly
media ed by ca aly ic ac i i ies.
Dissipa i e Sel -O ganiza ion, he
P ima y Sou ce o Molecula
O ganiza ion in he Cell
Reac i e cellula p ocesses ha e li le o do wi h he Chemis y
o Equilib ium. The undamen al cha ac e is ic o cellula
biochemis y is ha he ca aly ic eac ions, conside ed globally,
occu s a om he The modynamic Equilib ium. Unde hese
pa icula condi ions, i e e sible enzyma ic p ocesses aise he
spon aneous eme gence o sel -o ganized dissipa i e s uc u es
(sec ion “Dissipa i e Sel -O ganiza ion o Enzyma ic Ac i i ies,
he Main Sou ce o Molecula O ganiza ion in he Cell”).
Di e en ca aly ic mechanisms allow p ocesses a om
The modynamic Equilib ium, and one o he mos impo an is
he non-linea enzyme kine ics o many i e e sible enzymes wi h
allos e ic egula ion (Goldbe e , 2002, 2007).
Two p incipal ypes o sel -o ganized dissipa i e s uc u es
eme ge in he cell, empo al molecula hy hms, and spa ial
wa es. In empo al hy hms, molecula concen a ions luc ua e
o e ime in an oscilla o y manne (Figu e 1). E e y cell
appea s as a dynamic sys em in which cellula sel -des uc ion
and sel -cons uc ion happen ollowing complex quasi-s a iona y
pa e ns and un epea able molecula hy hms. On he o he
hand, he dissipa i e spa ial molecula wa es modula e he
cellula me abolic ac i i ies, synch onizing and egula ing
unc ionally di e en enzyma ic p ocesses. All hese sel -
o ganized beha io s a e unlikely o he Chemis y o he
The modynamic Equilib ium (De la Fuen e, 2010).
So, he cell is a me abolic sys em in which sel -cons uc ion
and sel -des uc ion occu ollowing complex ca aly ic hy hms,
mainly coo dina ed by spa ial molecula wa es.
The sel -o ganized dissipa i e s uc u es we e disco e ed by
Nobel Lau ea e Ilya P igogine (Nicolis and P igogine, 1977),
and hese dynamic p ocesses cons i u e he p ima y sou ce o
molecula o de in he cell. The concep o dissipa i e o de
is a undamen al issue o desc ibe he molecula - unc ional
a chi ec u e o li ing cells. Dissipa i e sel -assembling and
dissipa i e sel -o ganiza ion a e he wo pilla s o he molecula
o de and he eme gen unc ional complexi y o cells (De la
Fuen e, 2015). Howe e , being biologically essen ial, many issues
o cellula dissipa i e s uc u es emain unclea , which wa an
u he in es iga ion.
Cellula Enzyme O ganiza ion. Cellula
Me abolic S uc u e
A he cellula le el, enzyma ic ac i i y d ama ically depends on
he collec i e unc ional s uc u e o ca aly ic p ocesses which is
de ined by he wo undamen al p inciples ha connec he main
o ms o enzyme o ganiza ion in he cell: me abolic seg ega ion
and sys emicme abolic in eg a ion, ope a ing simul aneously
(sec ion “Dissipa i e Me abolic Ne wo ks and he Eme gence o
he Sys emic Me abolic S uc u e”).
Enzymes do no wo k independen ly o each o he in he
cellula molecula c owding, bu ins ead shape di e en ypes o
mul ienzyme associa ions, g ouped by hei me abolic asks and
ca aly ic oles. Thus all chemical eac ions ha occu in li ing
cells a e seg ega ed unc ionally (De la Fuen e, 2015).
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De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
Mo eo e , hese ca aly ic complexes in e ac e e sibly
wi h s uc u al p o eins and memb anes o igina ing
he modynamically open mic ocompa men s, in which
molecula hy hms can egula e he e iciency o he enzyma ic
eac ions in ol ed (De la Fuen e, 2010).
The e m Me abolic Subsys em was sugges ed in 1999 o e e
o hese sel -o ganized mul ienzyme se s in which complex quasi-
s eady-s a e beha io and molecula oscilla ions may eme ge
spon aneously inside he cell (De la Fuen e e al., 1999b).
These dissipa i e ca aly ic complexes (Figu e 1) ep esen
highly e icien nanos uc u es capable o pe o m au onomous
biochemical wo ks which cons i u e basic ca aly ic uni s o he
cellula o ganisms (De la Fuen e, 2015).
Mul ienzyme complexes a e o ganized in o dis inc modula
ne wo ks wi h speci ic and cohe en au onomous ac i i ies. A
a supe io le el, he me abolic ne wo ks (Figu e 2) appea o
be in eg a ed (sys emic me abolic in eg a ion) o ming a e y
complex dynamic supe -sys em, he CMS. Such global s uc u e
was obse ed o he i s ime in 1999 by analyzing DMN
h ough nume ical s udies (De la Fuen e e al., 1999b, 2008) and
was la e co obo a ed by lux balance analysis in p oka yo ic and
euka yo ic cells (Almaas e al., 2004, 2005;Almaas, 2007;De la
Fuen e, 2015).
In o ma ion P ocessing. The Second
Sou ce o Molecula O de in he Cell
A la ge numbe o expe imen al s udies ha e shown ha
unicellula o ganisms possess complex sel - egula o y beha io
o igina ed by biomolecula in o ma ion p ocessing, ano he
undamen al sou ce o o ganiza ion in he cell (sec ion
“Enzyma ic In o ma ion P ocessing, he Second Leading Sou ce
o Molecula O de in he Cell”).
The dissipa i e mul ienzyme complexes pe manen ly
send in o ma ion h ough me aboli e pa e ns be ween hei
di e en enzyme componen s. As a esul o he o e all
p ocess, hese enzyma ic assemblies ope a e as basic molecula
in o ma ion p ocessing uni s (Figu e 1). Thus, each dissipa i e
mul ienzyme complex de ines, a any ime, p ecise se s o
molecula ins uc ion luxes, and as a esul , each mul ienzyme
complex exhibi s well-de ined and speci ic me abolic ac i i ies
(De la Fuen e and Co és, 2012).
On he o he hand, a complex pa allel supe -sys em o
in o ma ion p ocessing appea s in he me abolic ne wo ks when
he sys emic ac i i y is conside ed (Figu e 2). CMS beha es as
a sel - egula ed dynamic en i y ha pe manen ly sends speci ic
egula o y signals o mul i-enzyme complexes make hem e ol e
in well-de ined and p ecise me abolic ac i i ies by in o ma ion
p ocessing, see Figu es 3–5(De la Fuen e e al., 2010, 2011, 2013;
De la Fuen e, 2015).
Molecula in o ma ion p ocessing allows he o ma ion in
he cellula me abolism o a ne wo k o unc ional links ha
eadjus he ca aly ic pa e ns, adap ing hem o he physiological
needs o cells du ing en i onmen al changes (sel - egula ion
p ocess). Besides, he in o ma ion gene a ed in hese p ocesses
highly inc eases he complexi y o cellula sys em. Physa um
polycephalum is a pa adigma ic example o he eme gence o
complex cellula beha io s media ed by in o ma ion p ocessing
in unicellula o ganisms. This mic oo ganism can disco e
he minimum-leng h op ion be ween wo dis an poin s in
a laby in h (Nakagaki e al., 2000;Nakagaki, 2001). No e
ha inding he sho es pa h p oblem in a maze needs a
igo ous ma hema ical analysis (Miyaji and Ohnishi, 2008).
P. polycephalum is also capable o imp o ing he selec ion
o he be e ou e con igu a ion ob ained by he sho es
S eine ’s minimum ee connec ions, hus de eloping adap ed
s a egies o maximize i s access o nu ien s (Nakagaki e al.,
2004a; 2004b). E en mo e, P. polycephalum achie es o sol e
di icul p oblems, o example, inding a high-quali y solu ion
o he p oblem o he a eling salesman, a ques ion which
is known o be NP-ha d (Aono e al., 2011a,b;Zhu e al.,
2011). This mul inuclea ed amoeba is capable o designing an
op imal ne wo k e y simila o he pu pose-in ended sys em
in he Tokyo ailway o ganiza ion (Te o e al., 2010). Du ing
he p ocess o adap a ion o di e en inpu s, P. polycephalum
succeeds memo izing changes in i s en i onmen , ecalling
hem la e o adap i s beha io o he new condi ions
app op ia ely, o example, an icipa ing a cold-d y pa e n in
he en i onmen 1 h be o e he change happens (Saigusa
e al., 2008). I has also been obse ed ha his p o is
accomplishes complex dilemmas o mul i-objec i e o aging
(Bonne , 2010;Dussu ou e al., 2010;La y and Beekman,
2011). Recen ly i has been shown ha P. polycephalum
is capable o de eloping a kind o udimen a y lea ning
(Boisseau e al., 2016). Molecula in o ma ion p ocessing has
been obse ed in nume ous o he biochemical sys ems (see
Supplemen a y Ma e ial 02).
Hop ield-Like Dynamics and Associa i e
Memo y
E icien in o ma ion p ocessing is impossible wi hou memo y
(sec ion “Hop ield-Type Sys emic A ac o s in Dissipa i e
Me abolic Ne wo ks. Cellula Sys emic Beha io s”). The p esence
o Hop ield-like dynamics cha ac e ized by associa i e memo y
in dissipa i e enzyma ic ne wo ks was nume ically e i ied
in 2013 (De la Fuen e e al., 2013). Such a memo y
would be a mani es a ion o eme gen p ope ies unde lying
he complex dynamics o he sys emic cellula me abolic
ne wo ks when dissipa i e enzyma ic sel -o ganiza ion and
molecula in o ma ion p ocessing ac oge he . This s udy was
he i s quan i a i e e idence ha an indi idual cell can
use associa i e memo y, which is suppo ed by epigene ic
mechanisms (De la Fuen e e al., 2013; De la Fuen e, 2015).
As a consequence o he eme gen Hop ield-like a ac o s, he
sys emic me abolism wo ks as a ully in eg a ed and indi idual
en i y (Figu es 6,7).
Associa i e memo y enables all o ganisms wi h a de eloped
ne ous sys em, om mollusks o humans, o lea n and
adap success ully o speci ic en i onmen al s imuli (Pa lo ,
1927;Mackin osh, 1983), bu un il now his ype o
lea ning has ne e been desc ibed in unicellula o ganisms.
Ve y ecen ly, pa e ns o locomo ion consis en wi h an
associa i e condi ioned beha io ha e been obse ed in wo
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gene-12-644615 May 15, 2021 Time: 15:2 # 22
De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
mic oo ganisms, A. p o eus and M. lening adensis (De la
Fuen e e al., 2019a). Bo h amoebae species we e capable
o linking wo simul aneous bu un ela ed pas e en s,
demons a ing a new mig a ion beha io ha p e ailed o
a ela i ely long ime, 44 minu es on a e age (Figu es 8,9).
This inding con i med in 2019 he p edic ion om he
p e ious s udies o 2013 on he eme gence o Hop ield-like
a ac o s wi h associa i e memo y a he sys emic cellula le el
(De la Fuen e e al., 2013).
Along wi h he in es iga ion o associa i e condi ioning in
single cells, a quan i a i e s udy on he dynamic cha ac e is ics
o he sys emic mo ili y o A. p o eus was ca ied ou ecen ly
h ough ad anced analysis o locomo ion mo emen s in
in ac and enuclea ed (cy oplas s) amoebae. This esea ch also
allowed he quan i ica ion o he impo ance o he nucleus
du ing he cellula mig a ion (De la Fuen e e al., 2019b).
Such s udy calcula ed speci ically he mo emen luc ua ions
along he locomo ion ajec o ies o he amoebae u ilizing he
“ ms ” me hod, a known echnique in S a is ical Mechanics
based on a wo k by Eins ein (1905), la e elabo a ed and
widely used o analyze ime-se ies. The esea ch e ealed ha
indi idual cells wi hou nuclei (cy oplas s) and in ac cells
displayed a simila mig a o y s uc u e mainly desc ibed by
non- i ial long- ange co ela ions. “This dynamic memo y
(non- i ial co ela ions) ep esen s a key cha ac e is ic o
A. p o eus mo emen s du ing cell mig a ion. I is wo h
no ing ha his empo al pe sis ence (co ela ions wi h
41.5 min on a e age) in cells and cy oplas s ma ches wi h
he Pa lo ian-like dynamic memo y (44 min on a e age)”
(De la Fuen e e al., 2019a).
The nucleus has been classically conside ed an essen ial
elemen go e ning cell mo emen , ne e heless di ec
quan i a i e e idence was lacking. The mig a o y analysis
o enuclea ed and non-enuclea ed amoebae desc ibed abo e
(B ingas e al., 2017;De la Fuen e e al., 2019b;De la Fuen e and
López, 2020) also demons a ed ha he absence o nucleus does
no impac he sys emic mo emen s o amoebae signi ican ly. An
independen g oup has eached a simila conclusion using o he
expe imen al me hods in human cells (G aham e al., 2018).
To summa ize, be ween he ex acellula space and
he DNA a dissipa i e sel -o ganized CMS exis s (De la
Fuen e, 2015). This supe -complex dynamic s uc u e
beha es as a decen alized in o ma ion p ocessing sys em,
“gene a ing se s o biochemical ins uc ions ha d i e each
enzyma ic ac i i y o a pa icula and p ecise dynamic
o change, allowing sel - egula ion and adap a ion o
he ex e nal medium. CMS pe manen ly sends a low
o molecula signals o he DNA-associa ed me abolism,
hus con ibu ing o o ming he complex ansc ip ional
sys em. These molecula lows allow he accu a e egula ion
o gene exp ession, so ha only he speci ic polypep ides
necessa y o he adap i e main enance o he CMS a e
syn hesized. Al oge he , bo h in o ma i e sys ems (CMS and
DNA) coo dina e he physiological de elopmen o he cell”
(De la Fuen e, 2015).
An ex ensi e s udy pe o med wi h DMN (a ound
15,210,000), o esea ch he mechanism behind he
eme gence o he CMS, allowed us o obse e ha
his global supe s uc u e is a p ope y common o all
SMSs wi h an high numbe o dissipa i e sel -o ganized
mul ienzyme complexes (De la Fuen e e al., 2009). The
undamen al ac o ha ensu es he spon aneous eme gence
o CMS is a high mul iplici y o dissipa i e me abolic se s
inside he cell.
The high edundancy o he enzymes (wi h an inc eased
numbe o copies) and he consequen mul iplici y o dissipa i e
sel -o ganized mul ienzyme complexes ha p e ail inside he cell
would de e mine he spon aneous o ma ion o he SMS.
A con inuous p ocess o molecula syn hesis and des uc ion
ep esen s housands o me abolic eac ions ha happen
pe manen ly and simul aneously in he cell, ensu ing he
eme gence, obus ness, and s abili y o he CMS.
The only possible scena io o cellula li e is a dynamic
sys em in pe manen sel -cons uc ion and sel -des uc ion
p ocess ha gua an ee he unc ionali y o a high numbe
o dissipa i e sel -o ganized mul ienzyme complexes.
The e is no o he al e na i e. This sophis ica ed and
massi e dynamics o endless molecula ans o ma ions
encompasses he whole me abolic sys em and cons i u es
he mos c i ical dynamic p ope y, essen ial and de ini o y,
o cellula li e.
The wo d “me abolism” comes om he G eek me abole
meaning “change” o “ ans o ma ion.” This wo d e lec s exac ly
he essen ial cha ac e is ic o he basic uni s o li e. Ra he
han a molecula geno heque (box o genes) in e olu ion, he
cell could be conside ed a singula dynamic me abolic uni
capable o sel -o ganize and sel - egula e in an endless p ocess o
molecula u no e .
“Me abolism can be conside ed he la ges known sou ce o
molecula complexi y in na u e” (De la Fuen e, 2015). Roughly
3,700 million yea s ago (Dodd e al., 2017), an excep ional
and singula me abolic dynamic eme ged om p ime al
ma e , cha ac e ized by a high s uc u al and unc ional
o de , imp obable o he Chemis y o Equilib ium. This
ex ao dina y molecula o ganiza ion pe pe ua es i sel by di ec
ansmission a e e e y mi osis, and he e is no scien i ic p oo
ha ano he pa allel me abolic o ganiza ion has eme ged “de
no o.”
Ac oss he millennia, many adap i e molecula mechanisms
ha e been acqui ed in he biological e olu ion by he CMS.
“Th ough he s uc u al and unc ional complexi ies, he
me abolic e olu ion has de eloped a la ge di e si y o
biochemical o ganiza ional o ms, anging om sophis ica ed
bac e ial me abolism, ia he complex enzyma ic ne wo ks,
cha ac e is ic o p o is s, o he ex ao dina y s uc u es
and p ocesses de i ed om he mul icellula euka yo ic
o ganiza ion, such as emb yogenesis o he neu al ne wo ks
p esen in highe mammals. The millions o li ing me abolic
species ep esen he inexhaus ible sou ce o complexi y
de eloped by he dynamic o ces o he cellula me abolism”
(De la Fuen e, 2015).
E e y unicellula o ganism esul s om he di ec and
unin e up ed ansmission o his ex ao dina y and singula
me abolic o ganiza ion. O e millions o yea s, sophis ica ed
F on ie s in Gene ics | www. on ie sin.o g 22 May 2021 | Volume 12 | A icle 644615
gene-12-644615 May 15, 2021 Time: 15:2 # 23
De la Fuen e e al. Sel -O ganiza ion and In o ma ion P ocessing
me abolic dynamics ha e e ol ed o o igina e complex biological
sup acellula s uc u es, ep oducing a di e en scales he
singula in insic o ganiza ion enclosed in i sel . . . up o
become sel -awa e.
AUTHOR CONTRIBUTIONS
ID, LM, MF, JC-P, JL, and IM pe o med he analysis and design
o he esea ch mapping. LM in ol ed in main unding. All
au ho s w o e he manusc ip and ag eed wi h i s submission. IM
concei ed, designed, and di ec ed he in es iga ion.
FUNDING
This wo k was suppo ed by he Uni e si y o Basque
Coun y UPV/EHU and Basque Cen e o Applied
Ma hema ics, g an US18/21.
SUPPLEMENTARY MATERIAL
The Supplemen a y Ma e ial o his a icle can be ound
online a : h ps://www. on ie sin.o g/a icles/10.3389/ gene.
2021.644615/ ull#supplemen a y-ma e ial
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F on ie s in Gene ics | www. on ie sin.o g 25 May 2021 | Volume 12 | A icle 644615