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Folate Trap - The science behind B12 deficiency

Ever had a situation where you got held responsible for something someone else did? Doesn’t feel that great right? Truth be told, it’s pretty common. It happens everywhere. Even in our bodies, after something as common as a sore throat, Rheumatic heart disease and nephritic syndrome are a few examples. 

A similar situation is rendered when the deficiency of Vitamin B12 renders Folic acid (Vitamin B9) inactive, a phenomenon commonly called, “The Folate Trap”.

Before we understand how one Vitamin deficiency makes another Vitamin inactive, let’s understand what roles both these molecules play in our bodies.

There are only two known biochemical reactions in our body that use Vitamin B12. The reaction we need to make ourselvesfamiliar for now, is the conversion of the amino acid Homocysteine to another amino acid, called Methionine, which is only structurally different from Homocysteine by one methyl group (CH3). This reaction is catalysed by an enzyme called “Methionine Synthase” which requires the presence of Vitamin B12 to function.

Now one of the chemical forms of Vitamin B12 is Methylcobalamin (The other one being the synthetic cyanocobalamin). The methyl group from methycobalamin gets transferred to Homocysteine, thus completing the reaction to Methionine. This reaction is important, because the active form of Methionine called S-Adenosyl Methionine, is required for important cellular functions like DNA synthesis. 

 
 

So after giving away it's methyl group, we are left with plain cobalamin now. Understandably, this form is pretty much useless. 

This is where folate comes in. Now folate is significant here because it's one of our body's most important “one carbon donors”. Folate is like the Oprah Winfrey of biochemistry- “You get a carbon, you get a carbon, everybody gets a carbon”. But usually, folate is in its inactive polyglutamate forms in circulation. 

One of the active form of folate, methyl-tetrahydrofolate, is the molecule of significance here, as it donates a methyl group to the now useless Cobalamin, converting it back to Methylcobalamin, thus making it capable of participating in Methionine synthesis again. 

 
 

But unlike cobalamin, the folate after donating its carbon atom isn’t completely useless. It gets shunted to another very important reaction, a reaction required for the de novo synthesis of nucleic acids (synthesised from scratch), which ultimately is required for DNA synthesis.

In this reaction the folate takes part as methylene-tetrahydrofolate, which will donate a carbon atom to the reaction forming thymidine, one of the 4 nucleic acids - the building blocks of life itself. This is catalysed by an enzyme called “Thymidilate Synthase”.

 
 

The form of folate that comes out of this reaction gets recycled back to methyltetrahydrofolate using another vitamin, Riboflavin, only to take part in this cycle all over again. 

So here's the entire outline of the folate cycle

 
 

So now let's assume that there’s no Vitamin B12. 

  • First of all, this is reflected by elevated levels of Homocysteine in circulation as the first reaction is cut off. 
  • Secondly, the form of folate that is required for DNA synthesis is not generated. 
 
 

So even though the fault is with Vitamin B12, the actual reason for all the clinical manifestations of its deficiency, called “Megaloblastic Anemia”, is the relative absence of Folate. “Trapped”, for no fault of it’s own. 

Author: Anirudh Murali (Facebook)

Sources and citations

1.Longo, Nicola. "Inherited Disorders of Amino Acid Metabolism in Adults." Harrison's Principles of Internal Medicine. 19th ed. Fig 434e-1.
2."Hematopoietic and Lymphoid Systems- Megaloblastic Anemias." Robbins Basic Pathology. 9th ed.: Elsevier-Saunders, 2013. 422-23.