Human choline dehydrogenase: Medical promises and biochemical challenges

Abstract

Human choline dehydrogenase (CHD) is located in the inner membrane of mitochondria primarily in liver and kidney and catalyzes the oxidation of choline to glycine betaine. Its physiological role is to regulate the concentrations of choline and glycine betaine in the blood and cells. Choline is important for regulation of gene expression, the biosynthesis of lipoproteins and membrane phospholipids and for the biosynthesis of the neurotransmitter acetylcholine; glycine betaine plays important roles as a primary intracellular osmoprotectant and as methyl donor for the biosynthesis of methionine from homocysteine, a required step for the synthesis of the ubiquitous methyl donor S-adenosyl methionine. Recently, CHD has generated considerable medical attention due to its association with various human pathologies, including male infertility, homocysteinuria, breast cancer and metabolic syndrome. Despite the renewed interest, the biochemical characterization of the enzyme has lagged behind due to difficulties in the obtainment of purified, active and stable enzyme. This review article summarizes the medical relevance and the physiological roles of human CHD, highlights the biochemical knowledge on the enzyme, and provides an analysis based on the comparison of the protein sequence with that of bacterial choline oxidase, for which structural and biochemical information is available.

Paths and determinants for Penicillium janthinellum to resist low and high copper

“…One of routes regulating the cellular CoA:acyl-CoA ratio is through metabolism of carnitine, glycine betaine and choline 57 . Glycine betaine is produced by the betaine aldehyde dehydrogenases (betA) 58 and through oxidation of choline by choline dehydrogenase(CHD) located in the inner membrane of mitochondria 59 . Carnitine is also produced by betA and buffers free CoA and Acyl-CoA pool through activated Acyl-CoA generated by carnitine acyltransferases(CA) 58 .…”

Structure of choline oxidase in complex with the reaction product glycine betaine

“…Choline oxidase contains FAD covalently linked to the protein through His99 . The enzyme is grouped into the glucose-methanol-choline (GMC) enzyme oxidoreductase superfamily (Cavener, 1992), which includes a variety of FAD-dependent enzymes that oxidize unrelated alcohols and share similar three-dimensional structures (Salvi & Gadda, 2013). The mechanism of action of bacterial choline oxidase has been extensively characterized (Quaye et al, 2008), with structural and mechanistic studies showing the importance of residues Ser101 (Yuan & Gadda, 2011), Glu312 (Quaye et al, 2008), His351 (Rungsrisuriyachai & Gadda, 2008), Val464 (Finnegan, Agniswamy et al, 2010;Gadda, 2012a), His466 (Ghanem & Gadda, 2005) and Asn510 (Rungsrisuriyachai & Gadda, 2010) in the active site.…”

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

“…Therefore, one can speculate that there are wide ranges of gene expression and regulation differences between BRCA1 dysfunction and the basal phenotype. To date, choline is among the well-studied essential nutrients that are involved in breast cancer; for example: (i) choline-containing compounds are significantly changed in breast cancer [9,10]; (ii) choline intake is inversely correlated with breast cancer risk [11-13]; and (iii) aberrant choline metabolism is often associated with malignant transformation, invasion, and metastasis of breast cancer [14-16]. Phosphatidylethanolamine N -methyltransferase ( PEMT ) is a small integral membrane protein that catalyzes the de novo synthesis of choline using S -adenosylmethionine as a methyl donor [17].…”