Part 4: Homocysteine and the Transsulfuration Pathway

Part 4: Homocysteine and the Transsulfuration Pathway

I’ve covered two of the four possible fates of homocysteine. The post will cover the third possible fate and that is the shunting of homocysteine into the transsulfuration pathway.

When there is optimal levels of SAM or elevated levels of oxidative stress, the will shift the bulk of homocysteine to the Transsulfuration pathway to provide glutathione, the body’s major antioxidant, as well as other important reactions I won’t be covering in today’s post. This isn’t an all or none response, just a change in the primary flow of the homocysteine.

GMC_15-032_Diagram_Image_Update01-min

Homocysteine is converted to cystathionine in the first step of the transsulfuration pathway. Two possible pathways/enzymes can be used to get to cystathionine.  The enzyme Cystathionine Beta Synthase (CBS) is used in the presence of Serine to produce Cystathionine and H2O.  The enzyme Cystathionine γ-Lyase (designated as CTH or CSE) is used in the presence of Cysteine to produce Cystathionine and Hydrogen Sulfide. Both reactions require adequate levels of B6. Elevated levels of SAM, Zinc and Hydrogen Peroxide will promote this reaction and Peroxynitrate and Testosterone will inhibit this enzyme.

SAM elevations will promote CBS enzyme upregulation by inhibiting the MTHFR and BHMT enzymes, essentially reducing the recycling pathways. SAM will have a stimulatory effect on CBS as well.

There are a few SNPs of the CBS enzyme that have been identified. There is some controversy whether these SNPs upregulate enzyme activity or downregulate enzyme activity. Clinically, I’ve seen numerous patients with CBS mutations C677T and A360A that have high levels of homocysteine, the opposite of what we should expect if these are upregulations. In searching the research, there seems to be similar findings.

My take on CBS activity is that there are multiple influences of CBS as with any enzyme. A person with a CBS SNP and plenty of B6 may show some upregulation at least temporarily. But since CBS is dependent on vitamin B6 and to some degree iron and serine, deficiencies in these co factors can halt or slow a CBS upregulation. A person’s upregulation of the enzyme may deplete their B6 stores slowing the enzymes activity.

As with any of the SNPs in the methylation cycle, you can’t just treat the SNP. You must look at the big picture and see what the other factors are that may have impact on the enzyme in question. A methylation panel and an organic acid/amino acid test can provide great insight along with a comprehensive metabolic panel and thorough patient history.

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