I’m reading Kilmer McCully’s book, “The Homoocysteine Revolution” and I’m enjoying it so far. It overlaps nicely with a lot of other material I’ve read and studied. I wanted to list the 3 enzymes he identifies as being linked to homocystinuria and 3 others that may be implicated. The goal is not to get hung up on the generic variants that cause problems for some people but to better understand the pathways from a nutritional perspective. This should help answer the question: how to people without problematic genetic variants avoid problems associated with elevated homocysteine levels (most notably arteriosclerosis)?
Here are 6 enzymes, the first 3 directly convert homocysteine to other amino acids, the other 3 listed here are enzymes which a deficiency of will limit one of those conversions.
- Cystathionine beta synthase (CBS, aka “cystathionine synthase”)
- CBS gene
- L-serine + L-homocysteine ⇌ L-cystathionine + H2O
- uses PLP/P5P (B6) as a cofactor
- defects in the genes for this enzyme tend to cause homocystinuria (type-I, classical type)
- Methionine synthase (MS, aka “methyltetrahydrofolate homocysteine methyl transferase”)
- MTR gene
- converts homocysteine to methionine by adding a methyl group
- uses 5-methyltetrahydrofolate, cobalamin, and zinc as cofactors
- defects in the genes for this enzyme can lead to homocystinuria (type-II), megaloblastic anemia, and hypomethionemia.
- Betaine-homocysteine S-methyltransferase (BHMT)
- BHMT and BHMT2 genes
- betaine + homocysteine → dimethylglycine + methionine
- uses zinc
- highest levels in liver and kidneys
- deletion of this gene in rats causes “hyperhomocysteinemia, altered choline metabolites, fatty liver, and hepatocellular carcinomas.”
- Methylenetetrahydrofolate reductase (MTHFR)
- MTHFR gene
- converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate used by methionine synthase
- defects in the genes for this enzyme can lead to homocystinuria (type-III)
- Methionine synthase reductase, mitochondrial (MSR)
- MTRR gene
- regenerates MS
- Methylmalonic aciduria and homocystinuria type D protein, mitochondrial (MMADHC)
- MMADHC gene
- converts cobalamin into adenosylcobalamin and methylcobalamin
- this can lead to homocystinuria by limiting MS activity due to lack of MeCbl
- this can also lead to methylmalonic acidemia due to the lack of AdoCbl
But what does this tell us? Well, there is an importance to getting folate, cobalamin, choline, zinc, and B6 in the diet in order to make sure none of these enzymes are limited by lack of nutrition. The form in which those nutrients are consumed also has importance. For those with MTHFR polymorphisms it is important to supplement with a L-5-MTHF supplement. For those with a MMADHC polymorphism it is important to supplement with methylcobalamin. However these forms are also probably the more beneficial form even for those without a genetic polymorphism.