Sulfur Metabolism

Image by Marco Costanzi from Pixabay

Those who suffer from sulfur intolerance may have bottlenecks at several different segments of the involved biochemical disposal pathways.

What follows is an overview of how where sulfur comes from, both in the body and from the diet, and its various fates for recycling, or elimination.

Sulfur Sources for Metabolism

Two amino acids (protein building blocks) include sulfur: cysteine and methionine. Protein turnover and dietary consumption together are the major sources of sulfur. A healthy young adult breaks down some 200 grams of tissue protein daily, though about 2/3 of that gets recycled into other proteins the body needs. Dietary intake is around a third of that amount, but if you subtract the amount of degraded protein that gets recycled, the diet is still a more substantial source.

Methionine and cysteine bound for degradation essentially enter the same pool. Methionine (from protein, as well as S-Adenosyl Methionine or SAMe, the end product of methylation, and homocysteine, a breakdown product of methylation) becomes cysteine via a process called transsulfuration which goes through the CBS enzyme and requires vitamin B6.

Cysteine that doesn’t get reincorporated into protein can then become a building block for glutathione. N-Acetyl Cysteine (NAC) is primed for this, as it has low oral bioavailability for other purposes—after the acetyl group is removed in the intestines, it appears that the cysteine goes straight to the liver, where it should turn into glutathione. (This is likely why most sulfur-sensitive individuals can nevertheless tolerate NAC, though not all.)

Otherwise, cysteine can escape via one of four pathways.

The Amino Acid Cysteine’s Breakdown Routes

The Taurine-Producing CDO (Cysteine dioxygenase) Pathway

Cysteine can get broken down into the amino acid taurine, requiring the cofactor Vitamin B6. Only a small amount of cysteine ends up here, though the amount that does largely depends upon dietary intake. If there’s not a lot of taurine to go around, the body will favor this pathway, and the kidneys will reabsorb it.

Once cysteine becomes taurine, the body can’t turn it into sulfate again… unless they have one specific type of bacteria overgrown in the gut, which can turn taurine into sulfite, and from there, into hydrogen sulfide gas (H2S) — more on this below. So someone intolerant of taurine supplementation might have overgrowth of that particular sulfate-reducing bacterial strain.

Worth a mention: H2S isn’t all bad. In small, local amounts, its oxidation can provide electrons to the mitochondria for ATP production. This is hormesis in action: the dose makes the poison.

The Sulfite-Producing CDO ((Cysteine dioxygenase)) Pathway

The other, much more heavily traveled arm of the CDO cysteine disposal pathway involves transamination, and does produce sulfite, the primary “toxic” sulfur metabolite. Sulfite is toxic because it tends to inhibit mitochondrial respiration, and because it’s reacts with cystine to for S-sulfocysteine, which mimics the excitatory neurotransmitter glutamate at the NMDA receptors. In the gut, sulfites also inactivate Vitamin B1 (thiamine), which can lead to a B1 deficiency, at least in theory.

Sulfite becomes sulfate via the SUOX enzyme. Together, these two steps require Vitamin B6, and molybdenum.

SUOX, meanwhile, exists on the mitochondrial membrane, and donates the electrons it takes from sulfite to the mitochondria for respiration. No waste here!

The PAPS Donor

Sulfate can be eliminated, or it can be recycled as a building block for various critical components in the body. Sulfate still has to get activated, though, which requires an ATP (so there has to be enough ATP to go around—those with mitochondrial dysfunction might be limited here). Then it eventually becomes 3′-phosphoadenosine-5′-phosphosulfate (PAPS).

PAPS then goes on to:

• Eliminate certain chemicals via SULT1A1, as well as phenols like salicylates
• Activate catecholamines, via SULT1A3
• Activate steroid hormones, including DHEA, via SULT2A1
• Inactivate thyroid hormones
• Produce cholecystokinin, signaling the gallbladder to release bile
• Eliminate bile acids, and rendering them less toxic to the gut
• Build structural components of the body such as chondroitin sulfate, keratan sulfate, and colonic sulfomucins, and glycosaminoglycans (GAGs)

Desulfuration

The CBS enzyme (with a B6 cofactor) shows up here too, along with several other enzymes. The desaturation pathway also eventually makes sulfite, which via SUOX (requiring a molybdenum) can become sulfate. This, as in the CDO arm, can either get eliminated, or recycled into PAPS as a structural building block.

Mercapturate Elimination

The sulfur found in cruciferous vegetables (called isothiocyanates) and the sulfur found in garlic and onions (called thiosulfinates) both react with glutathione (consuming it, as well as Vitamins B2 and B3), on their way to becoming mercapturate, which gets excreted.

But along the way, these superfoods activate Nrf2, which ultimately makes far more glutathione than the process consumes. (Meanwhile, cruciferous veggies are also a great source for DIM and I3C, important for Phase I liver elimination).

Preformed Sulfites

Sulfites can be added to various processed food products as preservatives. They’re most abundant in wine and dried fruits.  Since these enter at the sulfite step, they go straight to SUOX for elimination.

Preformed Sulfates

Sulfates can enter the body pre-formed, too—often from water sources, or inorganic mineral supplements complexed with sulfate.

A small amount of inorganic sulfates can be utilized by PAPS, but most of it ends up in the colon, where it can have a laxative effect. Also, sulfate-reducing opportunistic organisms can reverse-engineer sulfates to sulfites, on their way to making H2S. That’s in the colon, not in the small intestine, but dysbiosis in the colon can lead to SIBO.

Sulfated Polysaccharides

These include various food additives like carrageenan and gums, which are associated with leaky gut. Enzymes in the colon can release sulfates from these, where SRB organisms can turn them into sulfites on their way to H2S.

Sulfur Excretion (Or Reabsorption)

Most sulfur breakdown products arrive in the kidneys. The majority is in the sulfate form, and some 90% of it gets reabsorbed for use via PAPS. The other metabolites are eliminated, for the most part.

The sulfate reabsorption rate decreases substantially in cases of hypothyroidism, high cortisol, low Vitamin D levels, low potassium (hypokalemia), and metabolic acidosis. Interestingly, excessively high molybdenum or potassium citrate can also encourage sulfate wasting.

Causes for Sulfur Sensitivity

Given all of this, problems with sulfur metabolism seem to come down to:

1. SUOX slowdown mutations, cofactor deficiencies (molybdenum), or toxicity. Again, sulfites can poison the mitochondria, produce neurotoxic metabolites, and potentially create a deficiency in Vitamin B1.
2. CBS speed-up mutations can overwhelm SUOX with excessive sulfite production–or, over-methylation (as SAMe increases CBS activity dramatically, while decreasing MTHFR activity, in a feedback mechanism)
3. Excessive Sulfur-Reducing Bacteria, which can use sulfates as well as taurine as substrates, leading to gas, bloating, and SIBO.
4. Vitamin B6 deficiency. Four different enzymes involved in cysteine metabolism require Vitamin B6 as a cofactor. Deficiency can lead to bottlenecks, and sulfite accumulation.
5. Insufficient glycine — perhaps. Glutathione production requires glutamine and glycine in addition to cysteine, and glutamine is very abundant. Glycine is more likely to be the limiting step between the two—in which case, cysteine that hasn’t been recycled into protein will divert down the CDO pathways, where it may become sulfite primarily, on its way to sulfate.