MTHFR Part 7.4: Homocysteine continues…

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Curious about which genes influence homocysteine levels? The main player is the MTHFR gene, specifically the C677T variant—and having two copies of this mutation (homozygous) is the most concerning.

Everyone has two MTHFR genes, one inherited from each parent. Some people carry a mutation in one or both of these genes. If the mutation is present in only one gene, the person is called “heterozygous” for the MTHFR mutation. If both genes carry mutations, the person is “homozygous.”

The most common mutation is the MTHFR C677T, also known as the “thermolabile” mutation. Another frequent variant is MTHFR A1298C. For these mutations to cause problems, both gene copies usually need to be affected. Having just one mutated gene (heterozygous) typically has little to no medical impact.

Even when two mutations are present—such as two C677T mutations or one C677T and one A1298C—high homocysteine levels don’t always develop. While these mutations do affect homocysteine regulation, maintaining sufficient folate levels can effectively offset the impact.

In a paper published by Dr Joseph Pizzorno, ND, Editor in Chief, called “Homocysteine: Friend or Foe“, he lists the following:

Genes Directly and Indirectly Involved in Homocysteine Metabolism:

Symbol Gene Name Function
MTHFR Methylenetetrahydrofolate reductase Conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate
CBS Cystathionine-β-synthase Condensation of homocysteine and serine to form cystathionine
MTR Methyltetrahydrofolate homocysteine methyltransferase Remethylation of homocysteine to methionine
MTRR Methionine synthase reductase Reductive regeneration of cob(I)alamin cofactor required for the maintenance of MTR in a functional state
RFC1 Reduced-folate carrier 5-methyltetrahydrofolate internalisation in a cell
GCP2/FOLH1 Glutamate carboxypeptidase II Polyglutamate is converted to mono glutamate folate by the action of the enzyme folylpoly-γ-glutamate-carboxypeptidase (FGCPI), an enzyme expressed by GCP2
ENOS Endothelial nitric oxide synthase Conversion of l-arginine to l-citrulline and nitric oxide synthase (NO)
TC2 Transcobalamine II Transport of vitamin B12
SHMT1 Serine hydroxymethyltransferase I Reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate
TYMS Thymidylate synthase 5,10-methylenetetrahydrofolate and deoxyuridylate to form dihydrofolate and thymidylate
CTH Cystathionine-γ-lyase Hydrolysis of cystathionine to cysteine and α-ketoglutarate
MTHFD Methylenetetrahydrofolate dehydrogenase Conversion of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate
MTHFS Methenyltetrahydrofolate synthetase In the liver and kidney, it catalyses the conversion of betaine to dimethylglycine (DMG)
APOE Apolipoprotein E Mediates the binding, internalisation, and catabolism of lipoprotein particles
VEGF Vascular endothelial growth factor Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth
PON1 Paraoxonase I Hydrolyses the toxic organophosphorus. It also mediates an enzymatic protection of LDL against oxidative modification
BHMT Betaine-homocysteine methyltransferase In the liver and kidneys, it catalyses the conversion of betaine to dimethylglycine (DMG)
MAT1A Methionine adenosyltransferase IA Methionine to SAM by transfer of the adenosyl moiety of ATP to the sulfur atom of methionine
AHCY S-adenosy-l-homocysteine hydrolase Hydrolysis of S-adenosy-l-homocysteine to adenosine and homocysteine
CBL Cystathionine-β-lyase Conversion of cystathionine to homocysteine
F5 Coagulation factor V Cofactor for the factor Xa-catalyzed activation of prothrombin to the clotting enzyme thrombin
PAI1 Prothrombin activator inhibitor I Polyglutamate is converted to mono glutamate folate by the action of the enzyme folylpoly-γ-glutamate-carboxypeptidase (FGCPI), an enzyme expressed by GCP2

We are complex beings, with complex systems.

Alex is currently taking Methyl Care from Metagenic:

††As Metafolin®. Metafolin® is a registered trademark of Merck KGaA, Darmstadt, Germany.

We need to do a homocysteine test soon to see if any progress has been made in supporting his methylation cycle; however, this is a blood test, so it might be a bit difficult as Alex does not like having his blood taken.

For now, this is the end of our MTHFR research, even though there is so much more.

Some of the resources used during my research:

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