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The CBS Genes and Sulfur Metabolism: What to Know

CBS Gene Sulfur

If you’ve reached this article, you’re likely researching a family of genes, called the CBS (Cystathionine-Beta-Synthase) genes in order to better personalize nutrition. However, before I get into the meat of this post, I want to emphasize how common polymorphisms in the CBS genes are. Although the science of nutrigenomics is promising, you can’t tailor diet to just one gene, so don’t go making wholesale changes to your diet or health routine, just based on one genetic marker.

There has been a lot of buzz about the CBS family of genes and how they impact sulfur metabolism, both from supplements like glutathione, as well as from food sources, such as cabbage, broccoli, and other cruciferous vegetables, all of which are sulfur rich. 1

For our purposes at Gene Food, we are interested in how CBS SNPs should influence food and supplement choices, if they should at all, and what lab tests can help confirm potential high or low CBS activity.

Our custom nutrition plans report on CBS genes, but as part of a broader methylation scoring system rather than as recommendations tied to sulfur specifically. In our view, it is never a good idea to hyper focus on any one gene. With that out of the way, let’s delve into the world of CBS and sulfur.

What are the CBS genes and what do they do?

The CBS genes make an enzyme called cystathionine beta synthase (CBS).

CBS helps convert homocysteine into cystathionine as the first step in the transsulfuration pathway. 2 You can think of the transsulfuration pathway as the complicated chain of biochemical reactions the body uses to metabolize sulfur.

As the chart below demonstrates, perhaps the transsulfuration pathway’s most important job is to help produce glutathione, a powerful antioxidant we need to stay in good health. 3

Transsulfuration
A diagram of the transsulfuration pathway, an important process in the body’s detoxification process.

Diagram by Research Gate.

This Wikipedia article does a nice job of explaining its role of CBS in processing sulfur, which will be a key component of our dietary discussion below:

CBS occupies a pivotal position in mammalian sulfur metabolism at the homocysteine junction where the decision to conserve methionine or to convert it to cysteine via the transsulfuration pathway, is made. Moreover, the transsulfuration pathway is the only pathway capable of removing sulfur-containing amino acids under conditions of excess.

So, just as MTHFR genes convert homocysteine to methionine, CBS genes convert homocysteine to cystathionine.

They do this as part of our body’s methylation cycle, and in the process, they rid the body of excess sulfur containing amino acids.

For more on the biochemistry, check out this page, and this page.

The two extremes of CBS activity – down regulation and up regulation

To begin, it’s important to differentiate between CBS gene up-regulation, and down regulation.

Down regulation

Down regulation, or diminished CBS activity, results in poor sulfur metabolism, the pooling of sulfur groups, and potentially high homocysteine.

Low CBS activity is associated with diseases like homocystinuria. 4

Up regulation

Up-regulation of the CBS genes results in rapid sulfur metabolism that can correspond with low homocysteine.

When the CBS gene is highly active, the body cycles through homocysteine at a very rapid pace. Since the body makes ammonia as a byproduct of metabolizing sulfur, some have theorized that increased CBS activity results in higher levels of ammonia, which can cause a number of health issues. 5

But, here’s the thing:

The SNPs associated with CBS mutations (both slow and fast) are quite common

Before we get too bogged down in the land of CBS genes, it’s important to remember that these variants are carried by a large segment of the population.

To help understand the effect these various SNPs can have on CBS function I’ve pooled the important data into the simple table below.

SNP IDMajor/Minor (Risk)Risk Allele FrequencyRisk Allele Effect
rs2851391C/T38%High homocysteine/reduced CBS activity
rs234714C/T25%No Info
rs6586282C/T15%High homocysteine/reduced CBS activity
rs234709C/T45%No info
rs234706G/A28%Reduced homocysteine/increased CBS activity
rs5742905T/C0.02%Moderate increase in homocysteine/reduced CBS activity
rs4920037C/T13%Reduced CBS activity
rs28934891G/A0.03No info

One particular “up regulated” variant of interest is rs234706 or CBS C699T which I’ll discuss in more depth below.

CBS C699T and ammonia

For a very good overview on CBS up-regulation via C699T (the gene with the most data), take a look at this article by Mark London at MIT.

Mark discusses studies that have measured homocysteine levels in C699T genotypes. Many of these studies have not shown significant decreases in homocysteine with the T allele, important because low homocysteine would be evidence of increased CBS activity.

But lost in the shuffle in many discussions surrounding CBS is ammonia, because it’s ammonia that is a byproduct of sulfur metabolism. The practical implication for the everyday person with CBS gene SNPs would seem to be not only low homocysteine, but also awareness of elevated ammonia, regardless of whether the CBS SNP actually caused the ammonia level to rise.

Keeping in mind that ammonia can be high for reasons unrelated to CBS genes, what is the best lab test to measure ammonia?

To quote Mark:

Urinary ammonia is an even less reliable method for testing for CBS upregulation.  This is because most of the ammonia (NH4+) in urine is produced by the kidneys for ph regulation.  The ammonia that is produced elsewhere in the body, is usually detoxified by being converted to urea, which is then excreted.  This process mainly occurs in the liver, and the liver is quite capable of handling the large amount of ammonia that is produced in the body, which occurs due to the metabolization of amino acids.  The liver has to be able to do this, because the nervous system can only tolerate very low levels of ammonia.  Excess ammonia, i.e., hyperammonia, only usually occurs either when liver functioning has been greatly reduced, or where a genetic defect in the urea cycle exists.  Only by testing serum ammonia, can such a condition be diagnosed.

In light of the prevalence of these CBS gene variants, especially C699T, which has the most science examining up regulation, it seems unlikely to me that most people should not be taking extreme measures with their diets as the result of heterozygous CBS SNPs.

If you’re concerned that up-regulated CBS activity could be an issue, you could discuss an ammonia test with your doctor.

Dr. Aaron Gardner, BSc, MRes, PhD

Dr. Aaron Gardner, BSc, MRes, PhD is a life-scientist with a strong background in genetics and medical research, and the developing fields of personalized medicine and nutrition. Read his full bio here.

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