Radical-SAM dependent
nucleotide dehydratase (SAND),
rectification of the names of an
ancient iron-sulfur enzyme using
NC-IUBMB recommendations
Yuxuan Ji
1
, Li Wei
1
, Anqi Da
1
, Holger Stark
2
,
Peter-Leon Hagedoorn
3
, Simone Ciofi-Baffoni
4
,
Sally A. Cowley
5
, Ricardo O. Louro
6
, Smilja Todorovic
6
,
Maria Andrea Mroginski
7
, Yvain Nicolet
8
, Maxie M. Roessler
9
,
Nick E. Le Brun
10
, Mario Piccioli
4
, William S. James
5
,
Wilfred R. Hagen
3
and Kourosh H. Ebrahimi
1
*
1
Institute of Pharmaceutical Science, King’s College London, London, United Kingdom,
2
Institute for
Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Duesseldorf,
Germany,
3
Department of Biotechnology, Delft University of Technology, Delft, Netherlands,
4
Magnetic Resonance Center (CERM), University of Florence and Consorzio Interuniversitario
Risonanze Magnetiche di Metalloproteine (CIRMMP), Florence, and Department of Chemistry,
University of Florence, Florence, Italy,
5
Sir William Dunn School of Pathology, University of Oxford,
Oxford, United Kingdom,
6
Instituto de Tecnologia Química e Biológica António Xavier, Universidade
Nova de Lisboa, Av. da República–EAN, Oeiras, Portugal,
7
Institute of Chemistry, Technische
Universität Berlin, Berlin, Germany,
8
Université Grenoble Alpes, Grenoble, France,
9
Department of
Chemistry, Molecular Sciences Research Hub, Imperial College London, London, United Kingdom,
10
Centre for Molecular and Structural Biochemistry, School of Chemistry, University of East Anglia,
Norwich, United Kingdom
KEYWORDS
antiviral, innate immun system, dehydratase, nucleotide analogue, iron-sulfur [FeS]
cluster
Main text
In 1789, the influential French chemist Antoine-Laurent Lavoisier described his view of
science and its langague in his book Traité élémentaire de chimie. According to the Robert
Kerr’s translation it states (Lavoisier, 1790): “As ideas are preserved and communicated by
means of words, it necessarily follows that we cannot improve the language of any science
without at the same time improving the science itself; neither can we, on the other hand, improve
a science without improving the languageornomenclaturewhichbelongstoit.”This view
reminds us of Confucius’s earlier doctrine, the rectification of names (Steinkraus, 1980;Lau,
2000). Confucius believed that rectification of names is imperative. He explained (Steinkraus,
1980;Lau, 2000): “If language is incorrect, then what is said does not concord with what was
meant, what is to be done cannot be affected.Ifwhatistobedonecannotbeaffected,thenrites
and music will not flourish. If rites and music do not flourish, then mutilations and lesser
punishments will go astray. And if mutilations and lesser punishments go astray, then the people
have nowhere to put hand or foot. Therefore the gentleman uses only such language as is proper
for speech, and only speaks of what it would be proper to carry into effect. The gentleman in what
OPEN ACCESS
EDITED BY
Marie-Pierre Golinelli,
UPR2301 Institut de Chimie des
Substances Naturelles (ICSN CNRS),
France
REVIEWED BY
Teresita Padilla-Benavides,
Wesleyan University, United States
Soumi Ghosh,
Massachusetts Institute of Technology,
United States
*CORRESPONDENCE
Kourosh H. Ebrahimi,
SPECIALTY SECTION
This article was submitted to Cellular
Biochemistry,
a section of the journal
Frontiers in Molecular Biosciences
RECEIVED 30 August 2022
ACCEPTED 07 October 2022
PUBLISHED 21 October 2022
CITATION
Ji Y, Wei L, Da A, Stark H,
Hagedoorn P-L, Ciofi-Baffoni S,
Cowley SA, Louro RO, Todorovic S,
Mroginski MA, Nicolet Y, Roessler MM,
Le Brun NE, Piccioli M, James WS,
Hagen WR and Ebrahimi KH (2022),
Radical-SAM dependent nucleotide
dehydratase (SAND), rectification of the
names of an ancient iron-sulfur enzyme
using NC-IUBMB recommendations.
Front. Mol. Biosci. 9:1032220.
doi: 10.3389/fmolb.2022.1032220
COPYRIGHT
© 2022 Ji, Wei, Da, Stark, Hagedoorn,
Ciofi-Baffoni, Cowley, Louro,
Todorovic, Mroginski, Nicolet, Roessler,
Le Brun, Piccioli, James, Hagen and
Ebrahimi. This is an open-access article
distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms.
Frontiers in Molecular Biosciences frontiersin.org01
TYPE Opinion
PUBLISHED 21 October 2022
DOI 10.3389/fmolb.2022.1032220
he says leaves nothing to mere chance.”Inspired by these views, we
make the analogy that the progress of science and the language used
to describe it are two entangled electrons. This entanglement
highlights the importance of introducing systemic names for
enzymes using EC classification and the ever-growing problem of
protein names (McDonald and Tipton, 2021). Here, we tackle one
specific case of iron-sulfur ([FeS]) enzymes. We show that the
language used to describe a conserved [FeS] enzyme of the
innate immune system, i.e., viperin or RSAD2, is now inadequate
and disentangled from its science. We discuss that the enzyme has
cellular functions beyond its antiviral activity and that eukaryotic
and prokaryotic enzymes catalyse the same chemical reactions. To
prevent bias towards antiviral activity while studying various
biochemical activities of the enzyme and using scientifically
incorrect terms like “prokaryotic viperins,”we rectify the
language describing the enzyme. Based on NC-IUBMB
recommendations, we introduce the nomenclature
S-adenosylmethionine (SAM) dependent Nucleotide Dehydratase
(SAND).
Firstly, considering the progress in understanding the biology
of the enzyme in humans (Figure 1), the name “viperin”is no
longer adequate and should be avoided. In 1997, Hua Z., et al.
found that in response to human cytomegalovirus infection, the
mRNA level of a novel protein was elevated in human cells (Zhu
et al., 1997). The gene related to this mRNA was named
cytomegalovirus-induced human gene-5 (cig-5). In 2001, Chin
and Cresswell showed that interferons (IFNs) induce the
expression of the protein product of cig-5 (Chin and
Cresswell, 2001). This induction restricted the replication of
human cytomegalovirus, and the protein was localised to the
cytoplasmic face of the endoplasmic reticulum (ER) (Chin and
Cresswell, 2001). Because, at the time, nothing was known about
the chemistry of the enzyme, an abbreviation based on the
cellular localisation and antiviral activity was introduced,
“viperin”(virus inhibitory protein, endoplasmic reticulum-
associated, interferon-inducible) (Chin and Cresswell, 2001).
Subsequent studies showed that the expression of the protein
affects the life-cycle of many RNA and DNA viruses, including
Influenza (Wang et al., 2007), HIV-1 (Nasr et al., 2012), Hepatitis
C(Wang et al., 2012;Ghosh et al., 2020), Zika (Van der Hoek
et al., 2017;Panayiotou et al., 2018), and tick-borne encephalitis
(Panayiotou et al., 2018), among others. However, for each virus,
different mechanisms were proposed (Figure 1A). For example,
the enzyme affects lipid rafts (lipid microdomains on the cellular
membrane and enriched in cholesterol and sphingolipids (Ripa
et al., 2021)) and inhibits influenza virus (Wang et al., 2007)or
HIV-1 (Nasr et al., 2012) release. In the case of the Hepatitis C
virus, viperin expression appears to interfere with the binding of
the viral nonstructural protein NS5A with host hVAP22 (Wang
et al., 2012) or promotes proteasomal-dependent degradation of
viral NS5A (Ghosh et al., 2020). In the case of Zika and tick-
borne encephalitis viruses, the enzyme appears to induce
proteasomal degradation of the viral nonstructural protein
NS3 (Panayiotou et al., 2018). Finally, in the case of tick-
borne encephalitis virus and Dengue virus type-2, the enzyme
restricts viral RNA reproduction (Helbig et al., 2013;Upadhyay
et al., 2014).
Despite the established antiviral activity, many studies have
reported biological functions inconsistent with or unrelated to the
biology defined by the nomenclature “viperin”. Cresswell and
colleagues showed that the enzyme localises to lipid droplets
(Hinson and Cresswell, 2009) and enhances human
FIGURE 1
Human SAND has functions beyond its antiviral activity. (A) Various mechanisms of antiviral activity are proposed for human SAND. (B)
Expression of SAND affects the function and differentiation of various types of cells. HCV, hepatitis C virus; TBEV, tick-born encephalitis virus; DENV-
2, Dengue type-2 virus; NK, natural killer; IL, interleukin.
Frontiers in Molecular Biosciences frontiersin.org02
Ji et al. 10.3389/fmolb.2022.1032220
cytomegalovirus infection (Seo et al., 2011). In addition to
interferons, lipopolysaccharides were found to induce protein
expression (Olofsson et al., 2005). The proposal of multiple
mechanisms of antiviral activity prompted us to postulate that
the protein’s enzymatic activity regulates metabolism to affect
various cellular processes causing broad-spectrum antiviral
activity (Ebrahimi, 2018)(Figure 1B). This effect of the enzyme
on metabolism suggests a cellular function beyond its antiviral
activity. Indeed, many studies corroborate this proposal and
demonstrate that human SAND has a role in modulating
metabolism, regulating the activity/maturation of the immune
cells, and inducing the expression of immune genes (Figure 1B).
For example, the activity of SAND modulates central carbon
metabolism (Ebrahimi et al., 2020c), regulates thermogenesis in
adipose tissues (Eom et al., 2019), inhibits thiolase activity of the
trifunctional enzyme complex (a mitochondrial enzyme complex
with three activities: enoyl-CoA hydratase, 3-hydroxyacyl-CoA
dehydrogenase, and 3-ketoacyl-CoA thiolase) (Dumbrepatil et al.,
2020), and modulates cholesterol metabolism (Tang et al., 2016;
Grunkemeyer et al., 2021). It is required for optimal T helper two cell
response (Qiu et al., 2009) and chondrogenic differentiation via
CXCL10 protein secretion (Steinbusch et al., 2019). It has a role in
the innate system (Ebrahimi et al., 2022) and modules immune cell
function and maturation e.g., expansion of natural killer cells
(Wiedemann et al., 2020), dendritic cell maturation (Jang et al.,
2018), B cell hyperactivity (Zhu et al., 2021), and polarisation of
macrophages (Eom et al., 2018). Additionally, the enzyme’s
expression induces the expression of many immune genes
(Zhang et al., 2014).
Secondly, the nomenclature RSAD2 should be revised to fully
describe the chemistry of the enzyme relevant to its biological
function. By 2010, it became clear that human SAND has a
CxxxCxxC motif coordinating a [4Fe-4S] cluster, similar to many
members of the radical S-adenosylmethionine (SAM) enzymes
(Duschene and Broderick, 2010;Shaveta et al., 2010). As a result,
theHUGOGeneNomenclatureCommitteesuggestedthename
RSAD2 (radical-SAM domain containing 2) around this time. This
name can be easily confused with another radical-SAM enzyme of
unknown function (RSAD1), and it only partially describes the
SAM-dependent chemistry of the enzyme. In 2017, the structure of
mouse SAND was solved (Fenwick et al., 2017), confirming that it is
a radical-SAM enzyme. It was shown that the cytosolic iron-sulfur
biogenesis machinery is required to deliver and insert the [4Fe-4S]
cluster into the enzyme (Upadhyay et al., 2017). The expression of
human SAND in E. coli changed the cells’morphology, suggesting
the enzyme’s substrate is a metabolite common between eukaryotic
and prokaryotic cells (Nelp et al., 2017),and initial structural studies
proposed that the substrate is a nucleotide (Fenwick et al., 2017).
Subsequently, it was revealed that eukaryotic SAND could catalyse
the dehydration of CTP or UTP to 3ʹ-deoxy-3ʹ,4ʹ-didehydro (ddh)
analogues (Figure 2A)(Fenwick et al., 2020). In human
macrophages, the enzyme was found to produce ddhCTP (Gizzi
et al., 2018;Ebrahimi et al., 2020b). This novel nucleotide analogue
metabolite may act as a chain-terminator to inhibit viral replication
(IC
50
values ≥20 mM) (Gizzi et al., 2018). Subsequent studies
revealed that the expression of SAND and synthesis of ddhCTP in
HEK293 cells affects the cellular nucleotide pool and mitochondrial
function (Ebrahimi et al., 2020a). The enzyme in macrophages
modulates central carbon metabolism potentially by inhibiting the
NAD
+
-dependent activity of the glycolytic enzyme GAPDH
(Ebrahimi et al., 2020c)(Figure 2A). This function requires the
radical-SAM domain to produce ddhCTP since this nucleotide
analogue inhibits the NAD
+
-dependent activity of GAPDH
in vitro (Ebrahimi et al., 2020c). This immunometabolism
function of ddhCTP may regulate the immune response in
variousways(Ebrahimi et al., 2021,Ebrahimi et al., 2022).
Consistently, studies have shown that the expression of the
enzyme indeed primes the immune response (Zhang et al., 2014).
Finally, the use of the outdated nomenclature “viperin”can
introduce scientifically incorrect terms such as “prokaryotic viperin.”
Before 2017 little was done to isolate fungal and microbial SANDs
and characterise the chemical reaction catalysed by them. In 2017, a
thermostable fungal SAND from Thielavia terrestris was isolated
and characterised (Ebrahimi et al., 2017). It was hypothesised that
the fungal enzyme produces antiviral natural products and is a
suitable candidate for the biotechnological production of antiviral
lead molecules. The fungal SAND has promiscuous activity and
catalyses the dehydration of diverse nucleoside triphosphates
(NTPs), e.g., CTP, UTP, and 5-bromo-UTP, to their ddh
analogues via a mechanism requiring the transfer of an electron
and a proton (Figure 2B)(Ebrahimi et al., 2020b). Next, a number of
other groups characterised some microbial enzymes and showed
that they catalyse dehydration of various NTPs to their ddh
analogues (Bernheim et al., 2021;Lachowicz et al., 2021)
(Figure 2C). While the cellular function of these microbial
proteins is not fully understood, the chemical reaction catalysed
by SANDs can inhibit the activity of phage T7 RNA polymerase in
E. coli (Bernheim et al., 2021). These findings suggest that the
enzyme might have a cellular function and act as an antimicrobial/
antiviral defence system. The fungal enzyme was named TtRSAD2
(Ebrahimi et al., 2020b) due to the lack of a proper name, and studies
with bacterial enzymes (Bernheim et al., 2021) introduced a new
nomenclature, i.e., “prokaryotic viperin,”to describe prokaryotic
enzymes producing ddh analogues with antiviral activity (Bernheim
et al., 2021;Wein and Sorek, 2022). The term “prokaryotic viperin”
is not fit for purpose because it implies that bacteria and archaea
have endoplasmic reticulum, and interferons activate their immune
system. This assertion questions our fundamental understanding of
biology, i.e., prokaryotes do not have an endoplasmic reticulum and
interferon-mediated antiviral response.
A growing number of investigators are studying this new class of
enzymes across all domains of life (Figure 2D). Consequently,
different nomenclatures like RSAD2, viperin, prokaryotic viperin,
or viperin-like enzymes are being used by various investigators,
including us, to describe eukaryotic or microbial enzymes. As
discussed above, none of the existing nomenclatures accurately
Frontiers in Molecular Biosciences frontiersin.org03
Ji et al. 10.3389/fmolb.2022.1032220
describe the cellular function or chemistry in prokaryotes or
eukaryotes. Additionally, using various terminologies for enzymes
performing the same chemical reaction is confusing. Hence, we
strongly suggest the classification of the enzyme as a nucleoside
triphosphate dehydratase (NTPD, EC 4.2.1) and the nomenclature
SAND describing the SAM-dependent chemistry across all domains
of life. This classification and abbreviation to rectify the naming of
an ancient iron-sulfur enzyme should help the increasing number of
investigators studying the cellularfunctionorbiotechnological
application of these enzymes and the discovery of new enzymes
performing novel chemistries.
Author contributions
KE conceived the idea and wrote the manuscript together
with all the other authors.
Acknowledgments
All authors acknowledge the support from the European
Cooperation in Science and Technology (COST) Action
CA21115.
FIGURE 2
The nomenclature SAND (SAM-dependent Nucleotide Dehydratase) defines chemistry relevant to biology across all domains of life. (A) SAND
produces the nucleoside triphosphate analogue ddhCTP in humans. ddhCTP modulates metabolism affecting cell function and restricting viral
replication. (B) The proposed mechanism of dehydration of nucleoside triphosphates by SAND. The mechanism shows the transfer of a proton and
an electron from a conserved tyrosine. Alternatively, it is possible that proton transfer occurs via another amino acid residue. It is not clear if the
transfer of proton and electron occurs simultaneously (proton-coupled electron transfer). (C) SANDs from various organisms produce diverse ddh
analogues. (D) An increasing number of investigators study SANDs. The data were obtained from a search of nomenclature viperin and RSAD2 in the
title of articles. Google Scholar (scholar.google.com) and Web of Science search engines were used. N, nucleobase; C, cytosine; A, adenine; 5′-dAH,
5′-deoxyadenosine, 5′-dA·,5′-deoxyadenosyl radical.
Frontiers in Molecular Biosciences frontiersin.org04
Ji et al. 10.3389/fmolb.2022.1032220
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
Supplementary Material
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fmolb.
2022.1032220/full#supplementary-material
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