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Pyruvate Metabolism

Learning goals:
• Energy metabolism involves the oxidation of substrates with the capture of energy released as reduced
electron carriers  proton motive force  ATP
• Understand the varied metabolic fates of pyruvate
• Be familiar with the biological reasons for pyruvate being directed into pathways under different
conditions of energy demand, O2 availability, etc.
I. The BIG Picture
a. Energy metabolism = process that oxidizes food molecules and transfers the electrons to O2
b. Alkane (CH4)  Alcohol (CH3OH), Amine (CH3NH2), Alkene (CH2=CH2)  aldehyde or ketone
(CH2O)  carboxylic acid (HCOOH)  carbon dioxide (CO2)
i. Each step releases 2 electrons
c. 4 Major Fates of Pyruvate
i. Intense exercise in skeletal muscles: NADH must be reoxidized to NAD, glucose must be
resynthesized from pyruvate
1. Lactate dehydrogenase: Convert pyruvate to lactate in muscle (regenerates NAD),
transport lactate to liver to resynthesize glucose
a. Lactate dehydrogenase catalyzes the transfer of a hydride species H:
between NAD and C2 of pyruvate (the transfer is stereospecific and an
arginine and histidine residue in the enzyme aid catalysis)
2. Alanine aminotransferase: Convert pyruvate to L-alanine in muscle (use L-
glutamate as amino group donor-synthesis of L-glutamate converts NADH to
NAD), L-alanine sent to liver to resynthesize glucose
a. NADH is oxidized allowing glycolysis to continue
b. L-alanine (pyruvate equivalent) made, returned to liver and converted into
glucose
c. Ammonia (toxic product of amino acid degradation) converted into a
derivative that can be safely transported to the liver
ii. Pyruvate carboxylase: pyruvate converted to phosphoenolpyruvate (liver): Pyruvate 
Oxaloacetate  PEP
1. Biotin dependent enzyme, reaction occurs in two steps: 1. bicarbonate attached to
biotin (ATP-dependent), 2. carboxy-biotin reacts with pyruvate to transfer CO2 to
the C3 of pyruvate  oxaloacetate
iii. Pyruvate dehydrogenase complex: pyruvate oxidized to acetyl-coA (O2 plentiful)
***Acetyl-coA can no longer be used for the net synthesis of glucose***
1. Located in mitochondrial matrix, comprised of 3 proteins: pyruvate
dehydrogenase (cofactor TPP), dihydrolipoyl transacetylase and dihydrolipoyl
dehydrogenase (cofactor FAD)
2. Pyruvate is converted to acetyl-coA, the energy of oxidative decarboxylation
captured as NADH and the thioester of acetyl-coA, complex is tightly regulated
by NADH and acetyl-coA (inhibitors)
3. Deficiency of thiamine  beriberi (alcoholics)
a. TPP = cofactor used by enzymes that transfer activated aldehyde units
iv. Pyruvate decarboxylase: microbes convert pyruvate  acetaldehyde  ethanol