Pernicious anemia and role of Cobalamine in amino acid metabolism.

Pernicious anemia is a type of megaloblastic anemia that occurs due to abnormal absorption of vitamin B12 (cobalamine) from terminal ileum which is in turn due to decreased production of Intrinsic factor form Parietal cells of gastric mucosa.

This decrease in production of intrinsic factor from gastric parietal cells is due to autoimmune destruction of parietal cells where auto-antibodies are produced against Parietal cells and lead to their destruction and also cause atrophy of gastric mucosa. Genetically people with genotype HLA-DRB*03 and HLA-DRB*04 are more prone to this autoimmune disorder. Some evidence of association of H.pylori infection with pernicious anemia is also seen.

Intrinsic factor

Intrinsic factor is a glycoprotein that is produced form gastric parietal cells. This IF protein is encoded by GIF gene. When we ingest food that contains Vitamin B12, Vitamin B12 is separated from the food by peptic digestion. Gastric parietal cells release haptocorrin that binds to this cobalamine. Now gastric parietal cells release intrinsic factor. This intrinsic factor attaches itself with the cobalamine and separates it from HC. Enterocytes on the other hand have surface receptors for Intrinsic factor. Intrinsic factor attaches itself to those receptors and release cobalamine into the enterocytes. 80% of the cobalamine attaches itself to HC and go towards liver while 20% cobalamine in converted to Holotranscobalamine. The fraction of cobalamine that went to the liver is then release into the duodenum where it is degraded by pancreatic enzymes and HC and cobalamine are separated again. While the fraction of cobalamine that was converted to holotranscobalamine goes to various tissue cells for DNA synthesis.

Cobalamine

Cobalamine or vitamin B12 is a water soluble vitamin that acts in various important body functions. Chemical structure of this vitamin contains cobalt attached to cyanide. Major co-enzyme form of cobalamine is 5’-deoxyadenosyl cobalamine where cobalt-carbon bond is between 5’ carbon of 5’deoxyadenosyl moiety and cobalt of cobalamine.

Vitamin B12 is involved in almost all major metabolic functions of human body. This vitamin cannot be synthesized with the cellular machinery of our cells and thus it has to be taken into the diet. Bacteria have the ability to synthesize this vitamin. The food sources that contain this vitamin include meat, poultry, egg, milk and most important is liver.

Forms of cobalamine

There are various forms of cobalamine present naturally. It depends upon the side molecule to which cobalt is attached.

·         Cyanocobalamine

·         Hydroxycobalamine

·         Adenosylcobalamine

·         Methylcobalamine.

General functions of Cobalamine

Generally cobalamine has a major role in metabolism of fats and proteins. It also acts in the synthesis of folate and methionine. It has a major role in nerve function and production of RBCs. Also it has a role in DNA replication.

Role of cobalamine in amino acid metabolism

When amino acids are deaminated they yield alpha-ketoacid that feeds major metabolic pathways. There are 2 groups of amino acid based on whether or not their carbon skeleton can be converted to glucose.

1.       Glucogenic

2.       Ketogenic

The carbon skeleton of glucogenic amino acids yields pyruvate and 4-C 5-C intermediates of Kreb cycle. While the carbon skeleton of ketogenic amino acids yield acetyl-CoA and acetoacetate.

There are two major roles of Cobalamine in amino acid metabolism

1.       Conversion of homocystein to methionine.

2.       Conversion of propionyl CoA to Succinyl CoA.

Conversion of Homocystein to Methionine

For the sake of conversion of homocystein to methionine. Vitamin B12 is methylated to methylcobalamine by the use of folate. This methylcobalamine is then used to recycle homocystein to methionine. Actually Vitamin b12 act as a co-factor for the enzyme Methionine Synthase that is needed for the conversion of homocystein to methionine.

Conversion of propionyl CoA to Succinyl CoA

For conversion of Propionyl CoA to Succinyl CoA, cobalamine act as a cofactor for enzyme methylmalonyl CoA mutase. This enyme converts Propionyl CoA to Succinyl CoA. Pathway for the conversion of Propionyl CoA to Succinyl CoA is a part of oxidation of various other amino acids like threonine, isoleucine and methionine.

Effects of Vitamin B12 deficiency

In case of vitamin b12 deficiency, homocystein is not converted to methionine and its levels start to increase in blood. The increased levels of homocystein in blood caused endothelial cell damage. This can lead to atherosclerosis and endothelial dysfunction. Some observations also link the elevated blood levels of homocystein with oxidative stress state in our body. Researchers believe it can cause increased risk of CHF. Elevated levels of Homocystein are also associated with Migraine and Stroke.

On the other hand, when Vitamin B12 level decrease in our body, the conversion of Propionyl CoA to succinyl Co A decreases. This leads to decreased oxidation of Amino acids and major metabolic pathways of our body are disturbed. Including the ones associated with Nitrogenous base synthesis. This leads to Immature DNA formation. RBCs with immature DNA continue to grow in size and lead to macrocyte formation. That is why Macrocystic anemia occurs in case of Vitamin B12 deificiency.

Amino acids that are majorly affected by the deficiency of Vitamin B12 are Homocystien, Methionine, Threonine and Isoleucine. Other amino acids are also affected but these are the most effected ones.

Other sign and symptoms of Vitamin B12 deficiency include.

·         Generalized weakness

·         Headache

·         Tachycardia

·         Dyspnea

·         Anemia

·         Neurological manifestations