Sarcosine is a compound derived from the amino acid glycine and is involved in both its synthesis and degradation, and is an intermediate in the metabolism of choline to glycine. In cases of prostate cancer, the cancer cells seem to produce higher levels of sarcosine. Elevated levels of sarcosine found in the urine of patients with prostate cancer, and it has been suggested that these elevated levels are responsible for the development of the cancer. This pathway begins with choline’s transport into the mitochondrial matrix via xolute carrier family protein 44 A1 and the choline transporter-like protein 2. Once in the matrix, choline is oxidized to betaine aldehyde by choline dehydrogenase, and in the process reduces an acceptor. Betaine aldehyde is then converted to betaine by the addition of a water molecule by alpha-aminoadipic semialdehyde dehydrogenase. Following this, betaine is transported out of the mitochondria by an unknown transporter, where it then reacts with homocysteine to form dimethylglycine and L-methionine in a reaction catalyzed by betaine-homocysteine S-methyltransferase 1. The dimethylglycine is then transported back into the mitochondrial matrix by another unknown transporter, where it can react with tetrahydrofolate to form sarcosine and 5-methyltetrahydrofolic acid in a reaction catalyzed by dimethylglycine dehydrogenase. In at least some cases of prostate cancer cells, the SARDH gene is mutated, which encodes the sarcosine dehydrogenase protein. This can lead to an increase of sarcosine in the cells, as sarcosine dehydrogenase typically converts sarcosine to glycine, which is then converted to and from L-serine by serine hydroxymethyltransferase. With a non-functional or less functional enzyme, sarcosine levels will be increased, and serine and glycine levels will be reduced. A separate set of reactions outside of the mitochondria begins with the L-methionine produced by betaine—homocysteine S-methyltransferase 1, which is then converted to S-adenosylmethionine by a complex consisting of S-adenosylmethionine synthase and methionine adenosyltransferase. S-adenosylmethionine then reacts with glycine reversibly to form S-adenosylhomocysteine, as well as sarcosine. The expression of the gene encoding glycine N-methyltransferase, GNMT, can also be elevated in cancer tissues, leading to an increased concentration of sarcosine outside of the mitochondria as well.

Sarcosine Oncometabolite Pathway References