A: (B-02), Bioenergetics: Arsenic poisoning and Enzymes of the Central Metabolic Pathway

Original Question

 

 

 

Answer: (e)

 

Both enzymes (in fact, multienzymatic complexes) require Lipoic acid for their function.

 

Lipoic acid goes between oxidized and reduced forms during the reaction:

 

Lipoic acid

 

 

 

Dihydrolipoic Acid

 

 

Arsenic, mainly the trivalent form, reacts with the thiols groups (-SH) of dihydrolipoamide (dihydrolipoic linked to the enzymatic protein). Consequently, the interconversion between the reduced and the oxidized form of lipoic acid is not possible. It affects very important multifunctional enzymatic complexes.

 

 

Pyruvate dehydrogenase, alpha-keto glutarate dehydrogenase and branched chain amino acid dehydrogenase are very similar multienzymatic complexes that include lipoic acid in their structure, and have in common the following characteristics:

 

1. – All of them catalyze the global reaction:

 

Alphaketoacid  +  CoA + NADH.H⁺ ————>  acyl CoA + NAD⁺  + CO2

 

2.- All of them are formed by three enzymes that participates directly in the reaction and  five coenzymes:

           

Enzymes: A Ketoacid Decarboxylase

                               A Dihydrolipoyl Transacylase

                               A Dihydrolipoyl Dehydrogenase

 

            Cofactors: TPP, CoA, Lipoic acid, FAD and NAD.

 

3.- The mechanism of the reaction (and the Delta G) is the same

 

This graphic represents the reaction catalyzed by the complex of the alphaketoglutarate (or 2 oxo glutarate) dehydrogenase. Observe that the ability of oxidation and reduction of the thiols groups of lipoic acid is  key in the reaction.

  

 

 

 

As a consequence of the inhibition of the activity of these enzymatic complexes, pyruvate can not become acetyl CoA, the main feeder of Krebs cycle, and alphaketoglutarate can not continue to succinyl CoA in the Cycle. It affects deeply the production of energy in the cell, the membrane permeability becomes altered,  and Pyruvate, lactate and other metabolites accumulates. Other proteins and cell enzymes are also affected by the binding of Arsenite to thiols groups. Other forms of Arsenic can affect other processes in a different way.  Eventually, neurological disturbances appear and a multiorgan failure can occur that lead the person to death.

 

Arsenic poisoning can be accidental, occupational, suicidal or  homicidal.

 

More than 100 million people are at risk of this intoxication because of excessive arsenic in drinking water

     

  

Bangladesh is one of the regions where people is more exposed to arsenic in water. This song, describes how to avoid arsenic poisoning and explain misconceptions about the intoxication:

 

 

 

 

 

 

 

Children are a group at risk for accidental intoxication with rat poison containing arsenic.

 

The Borgias were a well know family that used Arsenic to solve discrepancies with other persons.

 

The death of Napoleon has been related to arsenic poisoning.

 

Some impressionist apparently developed Arsenic Intoxication due to the use of Emerald Green, a pigment based on Arsenic. It was Cezanne preferred pigment and Monet and Van Gogh used this pigment very frequently also. Cezanne’s Diabetes, Monnet’s blindness and Van Gogh’s disorders have been attributed to Arsenic intoxication as a consequence of the use of this pigment .

 

Paul Cezanne: Jas de Bouffan

 

 

 

More information about the toxic effects of Arsenic can be found in:

 

Marcus, S: Toxicity, Arsenic

 

 

 

Arsenic Toxicity: Physiologic effects