Main Menu

A 24- year-old boy presents with diarrhea, dysphagia, jaundice, and white transverse lines on the fingernails. The patient is diagnosed with arsenic poisoning, which inhibits which of the following enzymes ?

A) Citrate synthase

B)  Isocitrate dehydrogenase

C) Pyruvate Kinase

D) Alpha keto glutarate dehydrogenase

E) Succinate dehydrogenase

Answer-  The right answer is -D , Alpha ketoglutarate dehydrogenase complex. Arsenite (the trivalent form of Arsenic) forms a stable complex with the – thiol group of lipoic acid (Figure-1) making that compound unavailable to serve as a coenzyme. Arsenic poisoning is however due to inhibition of the enzymes that require lipoic acid as a coenzyme. The enzymes requiring lipoic acid  are- Pyruvate dehydrogenase complex, Alpha keto glutarate dehydrogenase complex and alpha keto acid dehydrogenase complex. The later enzymes is involved in the metabolism of branched chain amino acids. In the presence of Arsenite, induced lipoic acid deficiency causes decreased activity of said enzymes with the resultant accumulation of pyruvate, alpha keto glutarate and alpha keto acids of branched chain amino acids. There is inhibition of TCA cycle affecting brain, causing neurological manifestations and death.


Figure-1- showing structure of lipoic acid

Not only lipoic acid but all enzymes containing -SH groups are affected by Arsenic poisoning. Arsenate (Pentevalent form of Arsenic) can interfere with glycolysis at the step of Glyceraldeyde-3-P dehydrogenase thereby causing decreased ATP and NADH production by glycolysis, without inhibiting the pathway itself.The poison does so by competing with inorganic phosphate as a substrate for Glyceraldehyde-3-Phosphate dehydrogenase, forming a complex that spontaneously hydrolyzes to form 3-phosphoglycerate (Figure-2).Thus by bypassing the synthesis and dephosphorylation of 1,3 BPG, the cell is deprived of energy usually obtained from Glycolysis.


Figure-2- Arsenate competes with inorganic phosphate forming 1-Arseno-3- phosphoglycerate that spontaneously hydrolyzes forming 3-phosphoglycerate, thus no ATP is formed by substrate level phosphorylation in Glycolysis.

Arsenic  also competes with phosphates for adenosine triphosphate, forming adenosine diphosphate mono arsine, causing the loss of high-energy bonds.

In the given problem, only Alpha keto glutarate dehydrogenase complex is the enzyme requiring lipoic acid, the other enzymes like citrate synthase, Isocitrate dehydrogenase and Succinate dehydrogenase enzymes although are enzymes of TCA cycle but are unaffected in the arsenic poisoning. Similarly Pyruvate kinase (the enzyme catalyzing the last step of glycolysis ) is also not affected.

Evidences are there that it can cause inhibition of Hexokinase as well as Succinate dehydrogenase but are not widely proved.

Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!