Metabolite Proofreading in Carnosine and Homocarnosine Synthesis

Veiga‐da‐Cunha, Maria; Chevalier, Nathalie; Stroobant, Vincent; Vertommen, Didier; Schaftingen, Emile Van

doi:10.1074/jbc.m114.576579

Cited by 31 publications

(8 citation statements)

References 34 publications

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“…PM20D1 is one of five members of the mammalian M20 peptidase family, but remains entirely uncharacterized with respect to its endogenous substrates and products. Despite their annotation as metallopeptidases, the other four other mammalian M20 family members possess peptidase activity on a variety of small molecule substrates (Teufel et al, 2003; Van Coster et al, 2005; Veiga-da-Cunha et al, 2014). We therefore performed untargeted polar small molecule liquid chromatography-mass spectrometry (LC-MS) profiling of plasma from mice injected with AAV-GFP or AAV-PM20D1 viral vectors (Smith et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

Long

Svensson

Bateman

et al. 2016

Cell

207

219

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SUMMARY Brown and beige adipocytes are specialized cells that express UCP1 and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1+ versus UCP1- adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis; this pathway might be useful for treating obesity and associated disorders.

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Section: Resultsmentioning

confidence: 99%

The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

Long

Svensson

Bateman

et al. 2016

Cell

207

219

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“…Carnosine is synthesized by the enzyme carnosine synthase (CARNS), which is present in skeletal and heart muscle, as well as in certain regions in the brain (Veiga-da-Cunha et al 2014 ). The gene that encodes CARNS is ATPGD1 (Drozak et al 2010 ); however, the expression and distribution of this enzyme are poorly understood (Boldyrev et al 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic carnosine metabolism in the human kidney

et al. 2015

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Histidine-containing dipeptides like carnosine and anserine have protective functions in both health and disease. Animal studies suggest that carnosine can be metabolized within the kidney. The goal of this study was to obtain evidence of carnosine metabolism in the human kidney and to provide insight with regards to diabetic nephropathy. Expression, distribution, and localization of carnosinase-1 (CNDP1), carnosine synthase (CARNS), and taurine transporters (TauT) were measured in human kidneys. CNDP1 and CARNS activities were measured in vitro. CNDP1 and CARNS were located primarily in distal and proximal tubules, respectively. Specifically, CNDP1 levels were high in tubular cells and podocytes (20.3 ± 3.4 and 15 ± 3.2 ng/mg, respectively) and considerably lower in endothelial cells (0.5 ± 0.1 ng/mg). CNDP1 expression was correlated with the degradation of carnosine and anserine (r = 0.88 and 0.81, respectively). Anserine and carnosine were also detectable by HPLC in the renal cortex. Finally, TauT mRNA and protein were found in all renal epithelial cells. In diabetic patients, CNDP1 seemed to be reallocated to proximal tubules. We report compelling evidence that the kidney has an intrinsic capacity to metabolize carnosine. Both CNDP1 and CARNS are expressed in glomeruli and tubular cells. Carnosine-synthesizing and carnosine-hydrolyzing enzymes are localized in distinct compartments in the nephron and increased CNDP1 levels suggest a higher CNDP1 activity in diabetic kidneys.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-015-2045-7) contains supplementary material, which is available to authorized users.

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“…Many enzymes of intermediary metabolism catalyze side reactions and produce noncanonical metabolites that are then destroyed by metabolite-repair enzymes (13, 14). Mutations in metabolite-repair enzymes lead to the accumulation of side products (15–19) and in some cases cause metabolic diseases, like l -2-hydroxyglutaric aciduria (20, 21) and NAD(P)HX epimerase deficiency (22).…”

mentioning

confidence: 99%

Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency

Veiga‐da‐Cunha

Chevalier

Stéphenne

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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126

193

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SignificanceNeutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a noncanonical metabolite (1,5-anhydroglucitol-6-phosphate; 1,5AG6P) which is produced when glucose-phosphorylating enzymes erroneously act on 1,5-anhydroglucitol, a food-derived polyol present in blood. In patients or mice with G6PC3 or G6PT deficiency, 1,5AG6P accumulates and inhibits the first step of glycolysis. This is particularly detrimental in neutrophils, since their energy metabolism depends almost entirely on glycolysis. Consistent with our findings, we observed that treatment with a 1,5-anhydroglucitol-lowering drug treats neutropenia in G6PC3-deficient mice. Our findings highlight that the elimination of noncanonical side products by metabolite-repair enzymes makes an important contribution to mammalian physiology.

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Metabolite Proofreading in Carnosine and Homocarnosine Synthesis

Cited by 31 publications

References 34 publications

The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

Intrinsic carnosine metabolism in the human kidney

Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency

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