Pyruvate

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 Lglutamate 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