Which of the following enzyme dysfunction leads to lactic acidosis in thiamine deficiency?
Ans. d. Pyruvate dehydrogenase (Ref: Harper 28/e p321,473)In thiamine deficiency, pyruvate cannot be converted to acetyl Co-A a.s thiamine pyrophosphate is a coenzyme for pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl Co-A. Hence, excess of pyruvate is metabolized to lactate by lactate dehydrogenase. This results in lactic acidosis."Pyruvate, formed in the cytosol, is transported into the mitochondrion by a proton symporter. Inside the mitochondrion, it is oxidatively decarboxylated to acetyl-CoA by a multienzyme complex that is associated with the inner mitochondrial membrane. This pyruvate dehydrogenase complex is analogous to the alpha-ketoglutarate dehydrogenase complex of the citric acid cycle. Pyruvate is decarboxylated by the pyruvate dehydrogenase component of the enzyme complex to a hydroxyethyl derivative of the thiazole ring of enzyme-bound thiamin diphosphate, which in turn reacts with oxidized lipoamide, the prosthetic group of dihydrolipoyl transacetylase, to form acetyl lipoamide. Thiamin is vitamin B1 and in deficiency, glucose metabolism is impaired, and there is significant land potentially life-threatening) lactic and pyruvic acidosis. "--Harper 28/e p321Thiamin (Vitamin S1)Thiamin diphosphate (TDP)Q also known as Thiamin pyrophosphate (TPP)Q is biologically active & storage form of vitamin B1, formed by transfer of pyrophosphate group from ATP.Physiological Role:Thiamin has a central role in energy yielding metabolism and especially of carbohydrates.Thiamin requirements increase in excess intake of carbohydrates and its deficiency leads to decreased energy production.Thiamin (Vitamin B1)Thiamin diphosphate* Thiamin diphosphate is the coenzyme for:1. 3 multienzyme complexes that catalyze oxidative decarboxylation reactions:Branched-chain ketoacid dehydrogenaseQ involved in the metabolism of leucine, isoleucine & valineAlpha-ketoglutarate dehydrogenaseQ in the citric acid cyclePyruvate dehydrogenaseQ in carbohydrate metabolism2. Trans ketolaseQ reaction in the pentose phosphate pathwayThiamin triphosphateThiamin triphosphate has a role in nerve conduction: it phosphorylates, and so activates a chloride channel in the nerve membraneThiamine Deficiency Diseases:Chronic peripheral Neuritis, Beriberi & Wernicke Encephalopathy with Korsakoff's PsychosisBeriberiWernicke Encephalopathy with Korsakoff's Psychosis* Wet beriberi: Patients present with an enlarged heart, tachycardia, high-output congestive heart failure, peripheral edema & peripheral neuritisQ.* Dry beriberi: Symmetric peripheral neuropathy of the motor and sensory systems, with diminished reflexes. Neuropathy affects the legs most markedly* Infantile beriberi: Occurs in infants bom to thiamin deficiency mothers and show tachycardia, vomiting, convulsions & death.* Alcoholic patients with chronic thiamin deficiency also may have CNS manifestations known as Wernicke's encephalopathyQ.* Wernicke's encephalopathy: Consists of horizontal nystagmus, ophthalmoplegia (due to weakness of one or more extraocular muscles), cerebellar ataxia, & mental impairment* When there is an additional loss of memory and a confabulatory psychosis, the syndrome is known as Wernicke-Korsakoff syndromeQ.
Pyruvate carboxylase
Phosphofructokinase
Phosphoenol pyruvate carboxykinase
Pyruvate dehydrogenase
Vitamins