Role of Thiamine in HMP pathway

Case details

A 50 -year-old alcoholic male presents with pain, numbness, tingling and weakness in his feet. He is diagnosed with thiamine deficiency. Thiamine and ATP condense together to form   thiamine pyrophosphate, a cofactor important for the enzymes that catalyze oxidative decarboxylation of (α-keto acids) in the TCA cycle and also at one of the steps in pentose phosphate pathway, which out of the following enzymes requires TPP as a coenzyme ?

A) Glucose-6-P dehydrogenase

B) Transaldolase

C) Transketolase

D) 6-P-Gluconate dehydrogenase

E) Gluconolactone hydrolase

The correct answer is- C) – Transketolase.

Two reactions are catalyzed by Transketolase in HMP pathway.

Basic concept

The pentose phosphate pathway (also called Phosphogluconate pathway or hexose monophosphate shunt [HMP shunt]) is an alternative route for the metabolism of glucose.

This pathway consists of two phases: the oxidative (irreversible) phase and the nonoxidative (reversible) phase.

1) In the oxidative phase, there is oxidative decarboxylation of Glucose-6-P to form NADPH and Ribulose 5-phosphate. Ribulose is further isomerized to form Ribose-5-P (figure-1).This five-carbon sugar and its derivatives are components of RNA and DNA, as well as ATP, NADH, FAD, and coenzyme A.

2) In the nonoxidative phase, the pathway catalyzes the interconversion of three-, four-, five-, six-, and seven-carbon sugars in a series of nonoxidative reactions that can result in the synthesis of five-carbon sugars for nucleotide biosynthesis or the degradation of excess five-carbon sugars into intermediates of the glycolytic pathway (figure-1)

Overview of HMP pathway

 

Overview of HMP Pathway

Figure-1- HMP pathway consists of two phases, oxidative phase that leads to formation of Ribose-5-P by oxidative decarboxylation and Non oxidative phase that involves rearrangement process with the resultant formation of glycolytic intermediates. Glyceraldehyde-3-P (GAP) and Fr-6-P are intermediates of glycolysis. In other words, the glycolytic intermediates can also rearrange to form pentoses due to reversible nature of this phase and this holds true in skeletal muscle.

Summary of non oxidative phase

Summary of non oxidative phase

Reactions catalyzed by Transketolase

Reaction 1-

In the first reaction of non oxidative phase of HMP pathway, Transketolase catalyzes the transfer of the two-carbon unit comprising carbons 1 and 2 of a ketose (from Xylulose 5-phosphate) to the aldehyde carbon of an aldose sugar (ribose 5-phosphate), producing the seven-carbon ketose Sedoheptulose 7-phosphate and the aldose glyceraldehyde 3-phosphate. It therefore effects the conversion of a ketose sugar into an aldose with two carbons less and an aldose sugar into a ketose with two carbons more (Figure-2). The reaction requires Mg2+ and thiamine pyrophosphate (vitamin B1) as coenzyme.

 

Reaction -1 of Transketolase

Figure-2- Two phosphorylated pentoses (Keto and aldo pentoses) rearrange by transfer of two carbon units from Keto pentose (Xylulose-5-P) to Aldopentose (Ribose-5-P) to form phosphorylated aldo triose (Glycerladehyde-3-P) and phosphorylated keto heptose (Sedoheptulose-7-P).

Reaction 2 of Transketolase

In this reaction catalyzed by transketolase, Xylulose 5-phosphate again serves as a donor of glycoaldehyde. In this case Erythrose 4-phosphate is the acceptor, and the products of the reaction are fructose 6-phosphate and glyceraldehyde 3-phosphate (figure-3).Since the reactions of non oxidative phase are irreversible, the glycolytic intermediates can also rearrange to form pentoses.

Reaction-2 of Transketolase

Figure-3- Transketolase catalyzes the interconversion of  phosphorylated aldotetrose (C4) and ketopentose( C5) to form glycolytic intermediates , fructose-6-P (C6 ) and glyceraldehyde-3-P (C3).

As regards other options

A) Glucose-6-P dehydrogenase- Catalyzes the conversion of Glucose -6-p to 6-Phospho gluconolactone.

B) Transaldolase- catalyzes the transfer of a three-carbon Dihydroxyacetone moiety (carbons 1–3) from the ketose sedoheptulose -7-phosphate onto the aldose glyceraldehyde 3-phosphate to form the ketose fructose 6-phosphate and the four-carbon aldose Erythrose 4-phosphate. (Figure-1 and 4)

D) 6-P-Gluconate dehydrogenase-catalyzes the conversion of 6-phosphogluconate to Ribulose-5-Phosphate (figure-4)

E) Gluconolactone Hydrolase- catalyzes the conversion of 6-phosphogluconolactone to 6-Phosphogluconate (it is transiently formed, not shown in the figure-4

HMP pathway

Figure-4- Steps of HMP pathway.

Thus out of all Transketolase is the most appropriate option. Clinically, R.B.C. Transketolase activity is measured to determine the underlying deficiency of Thiamine. Thiamine deficiency is very common in Chronic Alcoholics.

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