FATE OF PYRUVATE OR Pyruvate Metabolism

Learning Objectives To enlist the possible reactions that the pyruvate may undergo To illustrate, how pyruvate enters into the Kreb’s Cycle To explain the mechanism involved in the conversion of pyruvate into acetyl CoA

FATE OF PYRUVATE Acetyl CoA (for further metabolism) oxidative decarboxylation Acetyl CoA (for further metabolism) +2H+ Lactate (anaerobic) Pyruvate +NH3 Alanine (amino acid synthesis) +CO2 Oxaloacetate (Gluconeogenesis) Ethanol + CO2 Alcoholic fermentation

Anaerobic Metabolism of Pyruvate Problem During glycolysis, NADH is formed from NAD+ But without O2, NADH cannot be oxidized to NAD+ If no more NAD+ is available (All NAD+ converted to NADH) Glycolysis will stop…

Anaerobic Metabolism of Pyruvate Solution Turn NADH back to NAD+ by making lactate (lactic acid) (oxidized) (reduced) (oxidized )

Anaerobic Metabolism of Pyruvate ATP yield Two ATPs (net) are produced in the anaerobic breakdown of one glucose The 2 NADHs are used to reduce 2 pyruvate to 2 lactate Reaction is fast and doesn’t require oxygen

Pyruvate Metabolism - Anaerobic Lactate NADH+H+ NAD+ Lactate Dehydrogenase Lactate can be transported by blood to liver and used in gluconeogenesis

Cori Cycle

Pyruvate metabolism Conversion to alanine and export to blood Keto acid Amino acid (ALT)

Alanine Cycle

Pyruvate metabolism (under aerobic conditions) Prepares pyruvate to enter into TCA cycle Electron Transport Chain TCA Cycle

Pyruvate metabolism (under aerobic conditions) SITE : Mitochondrion Pyruvate dehydrogenate(PDH) Complex Consists of: 2 Molecules of PDH 8 Molecules of Flavoprotein (with dihydrolipoyl dehydrogenase) One Molecule of dihydrolipoyl trans-acetylase

Pyruvate metabolism (under aerobic conditions) Coenzymes & Cofactors Required: TPP, Lipoic acid, CoASH, FAD, NAD+ and Mg++ Pyruvate transporter: For transport of pyruvate from cytoplasm into mitochondrion

Mechanism of conversion of pyruvate into acetyl CoA TPP TPP

Summary 2 Pyruvate 2 Acetyl CoA Energetics 2 NAD PDH complex 2 NADH + H 2CO2 2 Acetyl CoA Energetics 2NADH + H+  6 ATP + a high energy thio-ester group in the form of acetyl CoA

Inhibitors / Clinical aspects: 1. Arsenite / Hg++ ions bind with SH group of lipoic acid and inhibit PDH complex 2. Dietary deficiency of thiamine & chronic alcoholics  thiamine deficiency  decreased PDH activity 3. Inherited deficiency of PDH All these conditions   pyruvate   lactate

Regulation

Mechanism of conversion of pyruvate into acetyl CoA