University:
Boston University
Course:
GRS CH 633 | Physical Methods for Inorganic and Bioinorganic Chemistry
Academic year:

2021
Views:

125

Pages:

10
Author:

Rhett Clayton

OUTLINE: Introduction and review Transport Glycogenolysis Glycolysis Introduction & overview; 2 phases Phase I Phase II Summary: logic, energetics, labeling studies Other sugars Pasteur: Anaerobic vs Aerobic Fermentations Lactate-lactate dehydrogenase Acetoacetate decarboxylase Ethanol-pyruvate decarboxylase & alcohol dehydrogenase Pyruvate pyruvate dehydrogenase complex Fates of Pyruvate No Oxygen (anaerobic) sometimes anaerobic conditions Fermentation to acetate and other hydrocarbons in some strict anaerobes Strict anaerobe: Clostridium acetobutylicum Chaim Weizmann 1 Fermentation: Acetoacetate decarboxylase Dr. Kornberg: Lecture 02.01.17 (33:24-48:02)-Weizmann Fates of Pyruvate No Oxygen (anaerobic) sometimes anaerobic conditions Fermentation to acetate and other hydrocarbons in some strict anaerobes 2 Fermentation: Ethanol • Two-step reduction of pyruvate to ethanol • Humans do not have pyruvate decarboxylase. • Humans express alcohol dehydrogenase for ethanol metabolism, but is largely used in the reverse reaction, then aldehyde dehydrogenase takes it to acetate (recall the different forms with different Km values for why some people get flush). • Both steps require cofactors. – pyruvate decarboxylase: Mg++ and thiamine pyrophosphate (TPP) – alcohol dehydrogenase: Zn++ and NAD+ • CO2 produced in the first step is responsible for: – carbonation in beer – dough rising when baking bread Fermentation: Pyruvate decarboxylase Vitamin B1 TPP is a Common Acetaldehyde Carrier 3 Fermentation: Pyruvate decarboxylase TPP Is a Common Acetaldehyde Carrier :B-E • TPP forms a covalent bond with carbonyl carbon, forming an alcohol, and resulting in release of CO2. • TPP then allows rearrangement of and protonation of carbonyl carbon to release from complex. Fermentation: Pyruvate decarboxylase Like LDH, highly thermodynamically favorable (DG°’ = –6 kcal/mol) This reaction pulls the entire fermentation pathway. 4 Fermentation: Alcohol Dehydrogenase (ADH) His,2Cys: bind Zn2+ Ser/His: acid-base catalysis Zn2+ acetaldehyde Acid catalysis from Ser/His Fermentation: Alcohol Dehydrogenase (ADH) Base catalysis Acid catalysis 5 Fermentation: Ethanol 34:08) Humans are missing the gene for this enzyme. 34:08) Fermentation: Ethanol 34:08) 34:08) 6 Fermentation Glycolysis Occurs at Elevated Rates in Tumor Cells Warburg Effect • Tumor cells often grow faster than angiogenesis allows growth of capillaries to aerate them, resulting in anaerobic metabolism. • Tumor cells increased expression of LDH. • Use to generate intermediates • Compounds that inhibit key steps in glycolysis can kill cancer cells by limiting energy production. Fates of Pyruvate No Oxygen (anaerobic) Pyruvate Oxidation Oxygen available (aerobic) Dr. Kornberg: Lecture 7 Pyruvate Oxidation ONLY when O2 is present • This is why its called cellular respiration. • The end result will be the COMPLETE oxidation of carbon to CO2 Pyruvate Oxidation Glycogen-o-lysis Glyco-lysis Pyruvate Oxidation Krebs' Cycle Phosphorylation Oxidative 8 Pyruvate Oxidation Glycolysis 2 GLUCOSE DG′° = –35 kcal/mol (–146 kJ/mol) Respiration (+ 6 O2) DG′° = –678 kcal/mol 6 CO2 + 6 H2O (–2,840 kJ/mol) • Process in which cells consume O2 and produce CO2 • Provides more energy (ATP) per glucose than glycolysis • Process is slower than glycolysis • Evolutionary origin: developed about 2,500 mya • Used by animals, plants, and many microorganisms • Other fuel sources (lipids and AA) converge on respiration. Occurs in three major stages: 1) Pyruvate oxidation (acetyl CoA production) 2) acetyl CoA oxidation (CO2 production) 3) electron transfer and oxidative phosphorylation (H2O production) Pyruvate Oxidation Localization: In Eukaryotes, Respiration is Localized to the Mitochondria (Compartmentation) • Glycolysis occurs in the cytoplasm. Mitochondria • Pyruvate Oxidation and Citric Acid Cycle occurs in the mitochondrial matrix.† • Fantastic example of Compartmentation. • Oxidative phosphorylation occurs in the inner membrane. Inner membrane Outer membrane Cristae Matrix †Except succinate dehydrogenase, which is located in the inner membrane 9 Pyruvate Oxidation Conversion of Pyruvate to Acetyl-CoA • Net reaction: – oxidative decarboxylation of pyruvate • Means pyruvate will get oxidized as the carboxylate leaves (as CO2) – first carbons of glucose to be fully oxidized (C3 & C4) • Fairly simple reaction done by a complicated process. • Highly thermodynamically favorable/irreversible (DG°’ = –8 kcal/mol); mostly due to the loss of CO2 • Catalyzed by the Pyruvate Dehydrogenase Complex (PDC) – – – – – – Three main enzyme, each with multiple subunits: E1, E2, E3 Regulatory subunits: PD kinase & PD phosphatase Overall structure of E196, E224, E324 requires 5 coenzymes TPP, lipoic acid, and FAD are prosthetic groups. NAD+ and CoA-SH are co-substrates. PDC 10

Fates of Pyruvate Lecture Note

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