Core Metabolic Roadmap

Core Metabolic Roadmap How to get the molecules that are needed, when they’re needed. Ⓧinhibits  multiple steps reversibleKey: Glucose metabolism Q Glycerol 3-phosphate 6-Phosphogluconolactone Ribose 5-Phosphate Glycogen Glucose Glucose 6-Phosphate Fructose 1,6-Bisphosphate Dihydroxyacetonephosphate 1,3-Bisphosphoglycerate 3-Phosphoglycerate 2-Phosphoglycerate Fructose 6-Phosphate Phosphoenolpyruvate Glyceraldehyde 3-Phosphate Fructose 2,6-Bisphosphate glucose 6-phosphate dehydrogenase phosphoglucose isomerase triose phosphate isomerase glyceraldehyde 3-phosphate dehydrogenase phosphoglycerate kinase enolase hexokinase (isoform called glucokinase in liver & pancreas) ATP ADP glucose 6-phosphatase (mainly in liver & kidneys) Pi H2O fructose 1,6bisphosphatase 1 ATP ADP Pi H2O + fructose bisphosphate aldolase phosphoglycerate mutase Acetyl-CoA glycerol 3-phosphate dehydrogenase Glycerol Electron transport chain (ETC) & oxidative phosphorylation (oxphos) ATP ADP NADH NAD+ + Pi ⓍG6P (but not for glucokinase)  ⓍF26BP, AMP phosphofructokinase 1 F26BP, AMP, ADP ⓍATP, citrate uses NAD+/NADH in cytoplasm, FAD/FADH2 in mitochondria ATP ADP glycerol kinase  f ructose 2,6 - b is p hosphat ase 2 p hospho f ructo k inase 2 ATP ADP  Ⓧglucagon  Ⓧinsulin, X5P* Glucose 1-phosphate phosphoglucomutase ⓍNADPH  Pentose Phosphate Pathway Glycogen metabolism glycogen phosphorylase glycogen synthase UDP-glucose pyrophosphorylase UTP PPi UDP-glucose UDP  Ⓧglucagon  ⓍATP,glucose,G6P,insulin pyruvate kinase ATP ADP F16BP Ⓧacetyl-CoA, ATP, NADH, long chain fatty acids, alanine, glucagon & adrenaline in liver Oxaloacetate pyruvate carboxylase PEP carboxykinase GTP GDP CO2 acetyl-CoA ATP ADP + Pi HCO3 - citrate synthase Ⓧsuccinyl-CoA, ATP, NADH, citrate ADP Oxaloacetate Citrate Isocitrate α-ketoglutarate Succinyl-CoA Succinate Fumarate Malate citrate synthase (see above) isocitrate dehydrogenase isocitrate dehydrogenase NAD+ NADH GTP CO2 NADH aconitase α-ketoglutarate dehydrogenase CoA CoA succinyl-CoA synthetase GDP + Pi succinate dehydrogenase (CII of the ETC) H2O NAD+ malate dehydrogenase CoA fumarase NAD+ CO2 NADH ⓍATP ADP, Ca2+ Ⓧsuccinyl-CoA, NADH Ca2+ pyruvate carboxylase ATP ADP + Pi acetyl-CoA CO2 Citric acid cycle - aka tricarboxylic acid cycle (TCA) or Krebs cycle Different intermediates can be added & removed for/from the metabolism of various molecules (e.g. amino acids). Citrate can be removed from mitochondria, & converted into acetyl-CoA (& oxaloacetate) by citrate lyase for lipid synthesis. Malate can be removed from mitochondria & converted to oxaloacetate (by cytosolic MDH) for glucose synthesis.Glutamate various transaminases or glutamate dehydrogenase Aspartate α-ketoglutarate AST Pyruvate Lactate Alanine pyruvate dehydrogenase NADH NAD+ CO2 NADH NAD+ lactate dehydrogenase alanine transaminase Ⓧacetyl-CoA, ATP, NADH, fatty acids AMP, CoA, NAD+, Ca2+ glutamate α-ketoglutarate aspartate transaminase NADPH NADP+ Pi H2O 6-Phosphogluconate Ribulose 5-Phosphate NADPH NADP+ CO2H2O H+ gluconolactonase 6-phosphogluconate dehydrogenase Nucleotides Xylulose 5-Phosphate carbon scrambling via transaldolase and transketolase ribose 5-phosphate isomerase ribulose 5-phosphate 3-epimerase Oxidative phase Non-oxidative phase DNA, RNA, coenzymes FADH2 NADH & CII FADH2 FAD QH2 malic enzyme NADPH NADP+ CO2 intermembrane space mitochondrial matrix H H H cMDH = cytosolic malate dehydrogenase mitochondrial malate dehydrogenase oxaloacetate malate NAD+ + H NADH cMDH CI H 4 ADP + Pi CIII CIV + NAD+ H Q cytC H2O H 1/2 O2 + H H CII FAD + H H H 4H 2 FAD H H mGPDH Glycerol 3-phosphate Dihydroxyacetone phosphate (DHAP) cGPDH NAD+ + H oxaloacetate malate NAD+ various mitochondrial oxidative reactions α-ketoglutarate α-ketoglutarate glutamate glutamate aspartate CII = succinate dehydrogenase of the TCA cGPDH = cytosolic glycerol 3-phosphate dehydrogenase (NAD+-linked) mGPDH = mitochondrial glycerol 3-phosphate dehydrogenase (FAD-linked) cytosolic oxidative reactions Glycerol-3-phosphate shuttle Malate-aspartate shuttle succinatefumarate NADH FADH2 NADH FADH2 aspartate aspartate transaminase* AST aspartate transaminase* AST mMDH malateα-ketoglutarate antiporter aspartateglutamate antiporter It “costs” ~4 H+ per ATP made. *aspartate transaminase is aka aspartate aminotransferase and glutamic-oxaloacetic transaminase (GOT) CV (~3 used directly by CV (ATP synthase) and 1 for bringing in a Pi) ATP MDH cGPDH mGPDH FADH2 FAD NAD+ NADH Urea urea cycle Many of the above reactions take place in the cytosol (e.g. glycolysis), the mitochondria (e.g. the TCA cycle), or either one. The ETC, however, has strict localization in the inner mitochondrial membrane (IMM). Reducing equivalents from NADH generated in the cytoplasm must be shuttled into the mitochondrial matrix (e.g. via the malate-aspartate shuttle or the glycerol-3-phosphate shuttle).    + Odd-chain fatty acids Propionyl-CoA ATP ADP + Pi HCO3 - β-oxidation & acetyl-CoA NADH malate dehydrogenase NAD+ Malate Lactate fermentation is especially important under limiting oxygen conditions. Caution: The steps of glycolysis & gluconeogenesis from G3P to pyruvate occur 2X per glucose molecule! (ADP/ATP in some isoforms) The passing of electrons powers the pumping of protons, which creates a proton gradient that powers the production of ATP by ATP synthase (CV). DOI: 10.5281/zenodo.13338217 Fatty acids Ketone bodies Cholesterol Triacylglycerols (TAGs) Phospholipids acetyl-CoA carboxylase thiolase Malonyl-CoA Acetoacetyl-CoA HMG-CoA β-oxidation glycerol HMG-CoA synthase acetyl-CoA Ⓧmalonyl-CoA citrate lyase ATP ADP + Pi oxaloacetate CoA HCO3 - NADPH NADP+ 2 2 ATPADP + Pi Acetyl-CoA Lipid Metabolism Acetyl-CoA can’t cross the mitochondrial membranes, so separate pools of it are used in the mitochondria (where the TCA and fatty acid breakdown occur) and the and in the cytoplasm (where lipids are synthesized). Acetoacetyl-CoA thiolase cytoplasmic mitochondrial Steroids CoA P i Hexosamine pathway glycoproteins, glycolipids, etc. UDP-NAcetylglucosamine (UDP-GlcNAc) H2O Ⓧpalmitoyl-CoA, glucagon citrate, insulin mitochondrial malate transported to cytoplasm for gluconeogenesis