Because dichloroacetate inhibits the enzyme pyruvatedehydrogenase kinase, this compound has been used,with limited results, to treat lactic acidosis. The phosphorylation of the a-subunit of the pyruvate dehydrogenasecomponent of the pyruvate dehydrogenase complex bypyruvate dehydrogenase kinase causes complete loss ofenzymatic activity. Describe the theory behind the clinicaluse of dichloroacetate.

Because dichloroacetate inhibits the enzyme pyruvatedehydrogenase kinase, this compound has been used,with limited results, to treat lactic acidosis. The phosphorylation of the a-subunit of the pyruvate dehydrogenasecomponent of the pyruvate dehydrogenase complex bypyruvate dehydrogenase kinase causes complete loss ofenzymatic activity. Describe the theory behind the clinicaluse of dichloroacetate.

Biochemistry

6th Edition

ISBN:9781305577206

Author:Reginald H. Garrett, Charles M. Grisham

Publisher:Reginald H. Garrett, Charles M. Grisham

Chapter25: Nitrogen Acquisition And Amino Acid Metabolism

Section: Chapter Questions

Problem 22P

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One treatment for shock is to administer dichloroacetate (DCA), which inhibits the kinase associated with the pyruvate dehydrogenase complex. What is the biochemical rationale for this treatment?
Pyruvate dehydrogenase kinase (PDH kinase) catalyzes the phosphorylation of a specific Ser residue on the E1 subunit of the enzyme, rendering it inactive. One strategy to treat a pyruvate dehydrogenase deficiency disease involves administering dichloroacetate, a compound that inhibits pyruvate dehydrogenase kinase. How might this strategy be effective? The activity of the pyruvate dehydrogenase complex can be enhanced by inhibiting the kinase. O The activity of the pyruvate dehydrogenase complex can be enhanced by phosphorylation. O The activity of the pyruvate dehydrogenase complex can be enhanced by increasing concentrations of PDH kinase. O None of the above.
The same E1-Ez-E3 multienzyme structure found in the pyruvate dehydro- genase and the a-ketoglutarate dehydrogenase complexes is also used in the branched-chain a-ketoacid dehydrogenase complex, which participates in the catabolism of branched chain amino acids. Draw the reaction product when the following substrate is acted on by the branched chain a-keto acid dehydrogenase complex. H,C -C-COo- H,C
Lactic acidosis, weakness, fatigue, and sleepiness are observed in patients with genetic defects of one if the enzymes of pyruvate dehydrogenase complex. Explain The causes of the elevation of lactate in the blood of such patients and the emergence of hypoenergetic state. For this purpose write the following: a) scheme of the metabolic pathway of glucose metabolism, that includes this reaction and calculates the energetic effect of the process, outlining the reactions coupled with the use and formation of ATP. b) reaction of the reduction of pyruvate and explain the reason for its acceleration inpatients that have such genetic defects.
The enzyme, dihydrolipoamide dehydrogenase is present in both pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex. What type of reaction is catalyzed by these complexes? Describe the role of dihydrolipoamide dehydrogenase in these reactions.
phosphofructokinase is an allosteric enzyme that catalyzes the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate and represents the key control point in mammalian glycolysis. The enzyme is a homotetramer that is inhibited by ATP binding, activated by AMP binding, negatively regulated by phosphorylation, and competitively inhibited by 2,5-anhydro-D-glucitol-1,6-diphosphate. (a) Would you expect a plot of the initial rate of fructose 1,6-bisphosphate formation as a function of substrate concentration to show a sigmoidal or hyperbolic curve? (b) How would each of the regulators above affect the dynamics of the T state to R state equilibrium of phosphofructokinase? Briefly explain your reasoning. (c) If it were possible to isolate phosphofructokinase monomers in an active form, how would you expect the kinetics in (a) to be affected? How would the rate of the reaction be affected by ATP, AMP, and 2,5-anhydro-D-glucitol-1,6-diphosphate? Briefly explain your answers.
Refer to Figure, which indicates ∆G for each glycolytic reaction under intracellular conditions. Assume that glyceraldehyde-3-phosphate dehydrogenase was inhibited with iodoacetate, which reacts with its active site cysteine sulfhydryl group. Which glycolytic intermediate would you expect to accumulate most rapidly, and why?
What is the metabolic significance of the following observations? (1) Only the liver form of pyruvate kinase is inhibited by alanine, and (2) only gluconeogenic tissues contain appreciable levels of glucose-6-phosphatase.
The mechanism for the conversion from alpha kytoglutarate into succinyl CoA by alpha-ketoglutare dehydrogenase is analogous to the pyruvate dehydrogenase mechanism. Draw and show the major intermediates and arrow pushing for the enzyme-catalyze process for the conversion of alpha-ketoglutarate to succinyl CoA. Note: the carbanion of thiamine pyrophosphate nucleophillically attacks C-2 of the alpha-ketoglutarate, i.e., the carbonyl carbon of that substrate.
Describe the common characteristic among the reactions catalyzed by pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ID), and alpha-ketoglutarate dehydrogenase (KD) based on reversibility.
Arsenate (HAsO42-) can replace inorganic phosphate (Pi) in the reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase, causing Glyceraldehyde 3-phosphate to be directly converted to 3-phosphoglycerate (NADH is still formed). If a cell is expose to Arsenate, which of the following metabolites of glycolysis will not be detectable in the cell? 2-phosphoglycerate 3-phosphoglycerate Fructose 6-phosphate Glucose 6-phosphate 1,3-bisphosphoglycerate
One of the consequences of ethanol addiction is fattyliver disease, an illness in which liver cells accumulatetriacylglycerols, the esters derived from glycerol and fattyacids. Ethanol is oxidized in the cytoplasm of liver cells byalcohol dehydrogenase and aldehyde dehydrogenase to yieldacetate and 2 NADH. Acetate is then transported into themitochondrion, where it is converted to acetyl-CoA andmetabolized by the citric acid cycle. When alcohol is consumed in excessive quantities, the resulting high levels ofNADH cause metabolic abnormalities, one of which is highlevels of fatty acid synthesis. Fatty acid synthesis, also acytoplasmic process, uses acetyl-CoA as a substrate andNADPH as a reducing agent. Determine how a high level ofcytoplasmic NADH provides a source of NADPH for fattyacid synthesis.