Figure 3: The genes and intermediates of the pathway linking choline metabolism to the urea cycle. | Nature Communications

Figure 3: The genes and intermediates of the pathway linking choline metabolism to the urea cycle.

From: Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease

Figure 3

One route (green arrows) for the initial catabolism of choline is mediated by intestinal microbes and leads to the formation of trimethylamine (TMA). TMA is efficiently absorbed from the gastrointestinal tract and subsequently oxidized by the liver to form trimethylamine N-oxide (TMAO) through reactions catalysed by one or more of the flavin monooxygenase (FMO) family of enzymes. Alternatively (red arrows), choline can be oxidized to betaine through reactions catalysed by choline dehydrogenase (CHDH) and betaine aldehyde dehydrogenase (ALDH7A1). Betaine (also known as trimethylglycine) is demethylated to form dimethylglycine via the betaine-homocysteine S-methyltransferase enzymes (BHMT, BHMT2). This reaction simultaneously converts homocysteine to methionine. Dimethylglycine dehydrogenase (DMGDH) subsequently demethylates dimethylglycine to form sarcosine, which is then converted to glycine by sarcosine dehydrogenase (SDH) after removal of the remaining methyl group. Glycine is metabolized by a group of enzymes known as the glycine cleavage complex (GCC), which is the major route in animals for glycine degradation and the formation of ammonia (NH3) and carbon dioxide (CO2). NH3 is converted to carbamoyl phosphate, which enters the urea cycle (blue arrows) through the rate-limiting reaction catalysed by carbamoyl-phosphate synthase 1 (CPS1), or can be converted back to glycine through the GCC. Carbamoyl phosphate is metabolized by ornithine transcarbamylase (OTC) to form citrulline and subsequently argininosuccinate through a reaction catalysed by argininosuccinate synthetase (ASS). This is followed by the formation of L-arginine by arginosuccinate lyase (ASL). L-Arginine is used as a substrate for the production of nitric oxide or metabolized by arginase (ARG1) to form urea for excretion and ornithine for re-entry back into the cycle. Metabolites that were available for analysis are shown in black, whereas unmeasured metabolites are shown in grey.

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