Core Metabolic Roadmap

How to get the molecules that are needed, when they’re needed.
key:  Ⓧ inhibits multiple steps reversible
Glucose metabolism
Glucose
hexokinase glucose
ATP Pi 6-phosphatase
(glucokinase in liver)
Ⓧ G6P (but not ADP + Pi H2O (mainly in liver)
Pentose Phosphate Pathway for glucokinase)

oxidative phase Glycogen metabolism

6-phosphogluconate glucose 6-phosphate dehydrogenase Glucose 6-Phosphate UDP-glucose
dehydrogenase    Ⓧ NADPH glycogen synthase
NADP+ pyrophosphorylase  Ⓧ glucagon
phospho- phosphogluco-
nonoxidative phase gluconolactonase NADPH glucose mutase UTP PPi UDP
CO2 NADPHNADP+ H+ H2O
Ribulose 6-Phospho- 6-Phospho- isomerase Glucose UDP-glucose
Glycogen
5-phosphate gluconate gluconolactone 1-phosphate
glycogen phosphorylase
Fructose 6-Phosphate Ⓧ insulin   
phosphofructokinase 2
ribose 5-phosphate ribose 5-phosphate  Ⓧ glucagon
phosphofructokinase 1
isomerase 3-epimerase ATP Pi ATP
F26BP, AMP, ADP    


ADP + Pi H2O ADP + Pi
Ⓧ ATP, citrate         
Ribose Xylulose fructose 1,6- H2O      
5-Phosphate 5-Phosphate bisphosphatase 1 Pi
 fructose Fructose
Ⓧ F26BP, AMP 2,6-bisphosphatase 2
   Ⓧ insulin, X5P* 2,6-Bisphosphate
carbon scrambling via Fructose 1,6-Bisphosphate
transaldolase and transketolase fructose glycerol 3-phosphate
bisphosphate dehydrogenase
Nucleotides aldolase NADP+ NADPH
Glyceraldehyde Dihydroxyacetone- glycerol kinase
+ mGPDH
Glycerol
3-Phosphate phosphate Glycerol
glyceraldehyde NAD+ + Pi cGPDH 3-phosphate ADP + Pi ATP
triose phosphate
3-phosphate NADH
isomerase NAD+ NADH
dehydrogenase
uses NAD+/NADH in cytoplasm,
DNA, RNA, coenzymes 1,3-Bisphosphoglycerate FAD/FADH2 in mitochondria
phosphoglycerate kinase
ADP
ATP

3-Phosphoglycerate
phosphoglycerate mutase

2-Phosphoglycerate
enolase

Phosphoenolpyruvate
CO2
pyruvate kinase ADP PEP
GDP + Pi
F16BP ATP GTP carboxykinase
Ⓧ acetyl-CoA, ATP, NADH,
long chain fatty acids,
Oxaloacetate
alanine, glucagon (in liver) ADP + Pi pyruvate
ATP carboxylase
HCO3- acetyl-CoA

Pyruvate alanine transaminase

pyruvate
glutamate
CO2 carboxylase lactate dehydrogenase α-ketoglutarate
malic acetyl-CoA NADH pyruvate
NADPH
enzyme NAD+ dehydrogenase NAD+
Alanine
ATP Ⓧ acetyl-CoA, ATP, NADH
NADP +
ADP + Pi NADH, fatty acids CO2
Lactate AMP, CoA,
Urea CO2 citrate synthase NAD+, Ca2+
Ⓧ succinyl-CoA, ATP, NADH, citrate
acetyl-CoA carboxylase
urea
ADP Acetyl-CoA Malonyl-CoA
cycle
aspartate transaminase NADP+ NADPH
CoA
glutamate α-ketoglutarate oxaloacetate
ADP + Pi   Ⓧ NADPH
thiolase Lipid Metabolism
Aspartate AST Oxaloacetate citrate Citrate CoA
ATP
β-oxidation
synthase citrate lyase
Acetoacetyl-CoA Fatty acids
NADH acetyl-
MDH malate aconitase HMG-CoA CoA Ⓧ malonyl-CoA
glycerol
NAD+ dehydrogenase Isocitrate synthase CoA
Malate isocitrate HMG-CoA
NAD+
dehydrogenase
fumarase Ⓧ ATP NADH Triacylglycerols Phospholipids
H2O
Citric acid cycle - aka ADP, Ca2+ CO2 (TAGs)
tricarboxylic acid cycle Fumarate α-ketoglutarate Cholesterol Ketone bodies
succinate α-ketoglutarate
(TCA) or Krebs cycle
dehydrogenase dehydrogenase CoA

Various intermediates added & FADH2 CII (CII of the ETC) Ⓧ succinyl-CoA, NAD+
removed for/from the metabolism of NADH Steroids
various molecules (e.g. amino acids). FAD succinyl-CoA Ca2+ NADH
Succinate synthetase various
Malate can be removed from
mitochondria for glucose synthesis. Q
Succinyl-CoA CO2 transaminases
QH2
Citrate can be removed from CoA
mitochondria for lipid synthesis. GTP GDP + P
i
Glutamate
cytosolic oxidative
reactions Glycerol-3-phosphate shuttle
While many of the above reactions take place in the cytosol NADH
NAD+
(e.g. glycolysis), the mitochondria (e.g. the TCA cycle), or Malate-aspartate shuttle +H
either, the ETC has strict localization in the inner NADH & FADH2 cMDH = cytosolic cGPDH = cytosolic glycerol 3-phosphate
mitochondrial membrane. malate dehydrogenase cGPDH dehydrogenase (NAD+-linked)
aspartate oxaloacetate
aspartate Glycerol Dihydroxyacetone
Reducing equivalents from NADH generated in the aminotransferase NADH 3-phosphate phosphate (DHAP)
cytoplasm must be shuttled into the mitochondrial matrix. cMDH +H H
AST
H
NAD+ 4H H
α-ketoglutarate glutamate FADH2 4H 2H
intermembrane malate FAD
Electron transport space H H cytC
aspartate- malate-
chain & oxidative glutamate α-ketoglutarate
mGPDH
Q
phosphorylation antiporter antiporter CIV
mitochondrial CI CII CIII
malate
matrix α-ketoglutarate glutamate NAD +
1/2 O2 +
mMDH FADH2 FAD + H H H H H2O
AST mitochondrial NADH
malate
ADP
ATP + P
H
+H NAD+
aspartate dehydrogenase i
aminotransferase
fumarate succinate It “costs” ~4 H+
aspartate oxaloacetate CII = succinate per ATP made.
dehydrogenase of
various mitochondrial the TCA

oxidative reactions
mGPDH = mitochondrial
glycerol 3-phosphate
dehydrogenase (FAD-linked)