The Transulphuration Pathway
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Homocysteine isn’t always re-methylated, and isn't always a negative metabolite. In fact it can be recycled and used as a substrate for making some other important substances. This happens via the Transulphuration pathway, a 'drainage' route below the Methionine cycle.
CBS
Firstly, homocysteine is converted to an intermediate metabolite called cystathionine using the CBS enzyme (cystathionine beta synthase). This is used for several purposes, making:
- Cysteine - which can be used to make sulfate, glutathione or taurine, or
- Ammonia - a potential toxin, that is excreted via the urea cycle, or
- Alpha ketobutyrate
SNPs in CBS are often up-regulated. Although this might be seen as a positive for increasing cysteine and glutathione, in fact it is thought that the excess of cystathionine is overall negative and could flood and impair the other pathways below, or specifically increase ammonia. Also fast CBS can result in an excessive drain on homocysteine, resulting in less availability for re-methylation. Homocysteine levels may also look ‘normal’ on testing, cloaking genuine issues with methylation (a 'false negative'). This is another reason SAMe to SAH ratio can be more accurate than measuring homocysteine (as we mentioned in the Methionine Cycle article). Think of a fast CBS as plughole that homocysteine is disappearing down rather too quickly, and we are not always sure what it will be used for. Vitamin B6 is a cofactor and can also be depleted by increased CBS activity.
Support for fast CBS SNPs includes optimising the pathways above it, using vitamin B12 and choline to encourage homocysteine to be re-methylated. You can check out issues further by assessing for increased toxicity or altered amino acid levels. A urine or plasma amino acid profile can identify excess ammonia as well as levels of homocysteine, glutathione, cysteine, and taurine. Ammonia can be reduced by limiting animal protein, charcoal, and rebalancing gut flora using probiotics to inhibit bacterial production.
CTH
Some of the cystathionine is converted to the amino acid cysteine via CTH (cystathionine gamma-lyase), and then used for taurine, glutathione or sulfate synthesis. SNPs on CTH reduce its activity and can limit the pool of cysteine for all pathways, potentially affecting glutathione levels or sulphation. You can support this pathway with vitamin B6 as a cofactor, increase cysteine containing foods - eggs, pulses, seeds, meat and fish, or consider a supplement of NAC - N-acetyl cysteine.
Ideally some of the cysteine is eventually converted to sulfate which is used as a conjugate for sulphation, a vital phase 2 detoxification pathway that handles many different toxins including excess oestrogen. You can support levels of sulfate by increasing cysteine supply and reducing pressure on detoxification pathways by reducing toxic load and balancing sex hormones.
SUOX
It's not plain sailing down the sulfate pathway! There is a potential block as cysteine is converted to sulfite before sulfate. Sulfite is a chemical that can cause allergic type reactions in excess (and in fact can be used as a preservative on dried fruits, pre-prepared salads, and wine). Reactions to sulfites made internally or consumed can include asthma, nausea, hives and, in rare cases, more severe allergic reactions. It can also act as a significant neurotoxin. The enzyme SUOX (Sulphite Oxidase) converts the sulfites to the more useful sulfate form. SNPs in SUOX act as a block (especially if combined with the faster CBS SNP) and may result in a log jam of sulfites, causing reactions. Sometimes excess supplemented cysteine, high amounts of sulphur-containing foods (such as eggs, garlic, onions and brassicas), or dietary sulfites might cause or worsen the reaction. You can also test for presence of high sulfites in urine. Support SUOX SNPs with the cofactor molybdenum and caution with high sulphur foods and high dose NAC, MSM etc if used.
GSS
The cysteine might also be used to synthesise glutathione via GSS (Glutathione synthetase). Glutathione is important for protecting against oxidative stress and is used for phase 2 glutathione conjugation (detoxification). Glutathione synthesis could be affected by fast CBS, in effect flooding and overwhelming GSS, or a GSS SNP could directly reduce its activity. To support GSS SNPs reduce overall toxic load and oxidative stress, support energy and mitochondria as ATP is a cofactor, and you may consider supplementing glutathione.
MUT
MUT (methylmalonyl-CoA mutase) is a mitochondrial enzyme that converts methylmalonyl-CoA (from the earlier synthesised alpha ketobutyrate) to succinyl-CoA with adenosyl-cobalamin as a cofactor. This is used for a number of vital functions as an important enzyme in the Krebs cycle, for synthesis of heme, cytochrome P450 enzymes and nucleotides. You can support SNPs of MUT with Adenosyl B12.
