Coenzyme A Metabolism in Vitamin B-12—Deficient Rats

Brass, Eric P.; Tahiliani, Arun G.; Allen, Robert H.; Stabler, Sally P.

doi:10.1093/jn/120.3.290

Cited by 38 publications

(22 citation statements)

References 35 publications

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“…From a broader physiological perspective, all cells must control their pools of acyl-CoAs to avoid depletion of the pool of free CoA and/or synthesis of toxic metabolites (13,44). This suggests, by analogy with the work reported here and with earlier findings regarding acetyl CoA homeostasis (8), that there might well be other acyltransferase/deacylase systems that cells from all domains of life use to control the activity of acylCoA synthetases.…”

Section: Discussionsupporting

confidence: 58%

N-Lysine Propionylation Controls the Activity of Propionyl-CoA Synthetase

Garrity

Gardner

Hawse

et al. 2007

Journal of Biological Chemistry

188

229

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Reversible protein acetylation is a ubiquitous means for the rapid control of diverse cellular processes. Acetyltransferase enzymes transfer the acetyl group from acetyl-CoA to lysine residues, while deacetylase enzymes catalyze removal of the acetyl group by hydrolysis or by an NAD ؉ -dependent reaction. Propionyl-coenzyme A (CoA), like acetyl-CoA, is a high energy product of fatty acid metabolism and is produced through a similar chemical reaction. Because acetyl-CoA is the donor molecule for protein acetylation, we investigated whether proteins can be propionylated in vivo, using propionyl-CoA as the donor molecule. We report that the Salmonella enterica propionyl-CoA synthetase enzyme PrpE is propionylated in vivo at lysine 592; propionylation inactivates PrpE. The propionyl-lysine modification is introduced by bacterial Gcn-5-related N-acetyltransferase enzymes and can be removed by bacterial and human Sir2 enzymes (sirtuins). Like the sirtuin deacetylation reaction, sirtuin-catalyzed depropionylation is NAD ؉ -dependent and produces a byproduct, O-propionyl ADP-ribose, analogous to the O-acetyl ADP-ribose sirtuin product of deacetylation. Only a subset of the human sirtuins with deacetylase activity could also depropionylate substrate. The regulation of cellular propionylCoA by propionylation of PrpE parallels regulation of acetylCoA by acetylation of acetyl-CoA synthetase and raises the possibility that propionylation may serve as a regulatory modification in higher organisms.Protein acetylation is a ubiquitous means for the rapid control of diverse cellular processes (1, 2). Acetylation occurs at lysine residues, with acetyl-CoA (Ac-CoA) 5 serving as the acetyl group donor. In higher organisms, aberrant acetylation of lysine residues in histone tails correlates with diseases such as cancers and developmental disorders and may contribute to modulation of cell life span (3, 4). From bacteria to humans, N-Lys acetylation controls the activity of acetyl-coenzyme A synthetase (AMP-forming; Acs) and potentially that of other members of the AMP-forming family of enzymes (5-7). In Salmonella enterica, Acs is deacetylated by CobB, a member of the Sir2 family of NAD ϩ -dependent deacetylases (a.k.a. sirtuins) (8). Interestingly, strains of S. enterica lacking CobB deacetylase activity cannot grow on propionate because the propionyl-CoA synthetase (encoded by the prpE gene) that activates propionate to propionyl-CoA is not active (5, 9).Cells generate propionyl-CoA from several different processes, including the catabolism of odd chain fatty acids, the decarboxylation of succinate, the catabolism of amino acids (e.g. threonine), and the activation of propionate (10 -12). Propionate is a powerful inhibitor of cell growth that is widely used as a food preservative. Reports in the literature suggest that propionyl-CoA may be responsible for the cytotoxic effects of propionate. Although the direct effects of propionyl-CoA are unclear, it is clear that cells avoid accumulating this metabolite (13-15). The cell maintains...

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Section: Discussionsupporting

confidence: 58%

N-Lysine Propionylation Controls the Activity of Propionyl-CoA Synthetase

Garrity

Gardner

Hawse

et al. 2007

Journal of Biological Chemistry

188

229

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“…When methylmalonyl-CoA mutase activity is de- creased due to the depletion of its coenzyme, AdoCbl, the hepatic levels of propionyl-CoA and methylmalonylCoA are greatly increased, resulting in the abnormalities in pyruvate and fatty acid oxidation, gluconeogenesis and ureagenesis in the liver (6,(19)(20)(21). In addition, methylmalonic acid is produced by the hydrolysis of methylmalonyl-CoA, accumulated in the plasma and tissues, and excreted abnormally into the urine (methylmalonic aciduria) (1,2,16).…”

Section: Resultsmentioning

confidence: 99%

Abnormal Increase in the Expression Level of Proliferating Cell Nuclear Antigen (PCNA) in the Liver and Hepatic Injury in Rats with Dietary Cobalamin Deficiency

Nakao

Kono

Adachi

et al. 2006

J Nutr Sci Vitaminol

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Summary Dietary cobalamin (Cbl; vitamin B 12 ) deficiency resulted in severe growth retardation in rats, and body weight in the Cbl-deficient rats at 20 wk of age was significantly lower compared with the age-matched Cbl-sufficient control rats. In contrast, liver weight, when normalized to body weight, was greater in the Cbl-deficient rats than in the controls ( p Ͻ 0.05). The expression level of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, in the liver was significantly enhanced in the deficient rats, suggesting that cell proliferation is abnormally activated in the liver under Cbl-deficient conditions. In addition, plasma alanine aminotransferase (ALT) activity, a marker for hepatic injury, was also significantly elevated in the deficient rats. When L -carnitine, which is used clinically for the treatment of Cbl-deficient patients with methylmalonic aciduria, was administered to the Cbl-deficient rats by intraperitoneal injection twice per day for 2 wk (each 0.5 mmol), the amount of methylmalonic acid excreted into the urine was significantly reduced, and the plasma ALT activity was lowered to a normal level. However, the PCNA expression in the liver was barely influenced by the treatment with carnitine. In contrast, when the deficient rats were fed an L -methionine-supplemented diet (4 g of L -methionine per kg of the diet) for 2 wk, the increased expression of PCNA was normalized.

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“…Key words: organic acidurias * animal model * cobalamin analogues -mitochondrial function * mitochondrial biogenesis Vitamin B 12 (cobalamin) deficiency leads to decreased activity of the cobalamin-requiring enzymes methylmalonyl-CoA mutase and methionine synthetase (1). Decreased activity of methylmalonyl-CoA mutase results in accumulation of methylmalonyl-and propionyl-CoA, and methylmalonic aciduria (2)(3)(4). This defect is analogous to the metabolic defect in patients with hereditary methylmalonic acidurias.…”

Section: Introductionmentioning

confidence: 97%

“…This defect is analogous to the metabolic defect in patients with hereditary methylmalonic acidurias. The vitamin B 12-deficient rat has provided a useful animal model for the human methylmalonic acidurias and allowed the investigation of hepatic metabolism in the presence of this specific, metabolic insult (4)(5)(6). Dietary vitamin B 12 deficiency is difficult to achieve, and the resulting metabolic defect shows a high variability between treated animals (7,8).…”

Section: Introductionmentioning

confidence: 99%

Increased hepatic mitochondrial capacity in rats with hydroxy-cobalamin[c-lactam]-induced methylmalonic aciduria.

Krähenbühl¹,

Ray²,

Stabler³

et al. 1990

J. Clin. Invest.

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IntroductionTreatment of rats with the vitamin B12 analogue hydroxy-cobalaminic-lactaml (HCCL) impairs methylmalonyl-CoA mutase function and leads to methylmalonic aciduria due to intracellular accumulation of propionyl and methylmalonyl-CoA.Since accumulation of these acyl-CoAs disrupts normal cellular regulation, the present investigation characterized metabolism in hepatocytes and liver mitochondria from rats treated subcutaneously with HCCL or saline (control) by osmotic minipump. Consistent with decreased methylmalonyl-CoA mutase activity, 14C02 production from 1-"4C-propionate (1 mM) was decreased by 76% and 82% after 2-3 wk and 5-6 wk of HCCL treatment, respectively. In contrast, after 5-6 wk of HCCL treatment, "4CO2 production from 1-"4C-pyruvate (10 mM) and 1-'4C-palmitate (0. Vitamin B 12 (cobalamin) deficiency leads to decreased activity of the cobalamin-requiring enzymes methylmalonyl-CoA mutase and methionine synthetase (1). Decreased activity of methylmalonyl-CoA mutase results in accumulation of methylmalonyl-and propionyl-CoA, and methylmalonic aciduria (2-4). This defect is analogous to the metabolic defect in patients with hereditary methylmalonic acidurias. The vitamin B 12-deficient rat has provided a useful animal model for the human methylmalonic acidurias and allowed the investigation of hepatic metabolism in the presence of this specific, metabolic insult (4-6). Dietary vitamin B 12 deficiency is difficult to achieve, and the resulting metabolic defect shows a high variability between treated animals (7, 8). An alternative methodology to induce decreased activity of methylmalonyl-CoA mutase is treatment with hydroxy-cobalamin [c-lactam] (HCCL),' a synthetic vitamin B 12 analogue (4-6). Rats treated with HCCL develop decreased hepatic vitamin B 12 levels (4), decreased methylmalonyl-CoA mutase and methionine synthetase activity (6), and decreased propionate metabolism with an increased renal excretion of methylmalonic acid (4-6).Increased hepatocellular propionyl and methylmalonylCoA concentrations inhibit several metabolic activities, including gluconeogenesis (9, 10), urea synthesis (9, 11) fatty acid oxidation (11, 12) and pyruvate decarboxylation (13, 14). In contrast, in rats with chronic accumulation of propionyl and methylmalonyl-CoA induced by dietary vitamin B 12 deficiency, gluconeogenetic and ketogenetic responses to fasting were intact in vivo (4), suggesting compensatory mechanisms that mitigate the toxic effects of accumulated acyl-CoAs. One compensatory mechanism in rats with dietary and functional vitamin B 12 deficiency is increased hepatic total CoA concentration (4, 15).To further study hepatic metabolism under conditions of impaired methylmalonyl-CoA mutase activity, hepatic mitochondrial function in HCCL-and saline-treated rats was characterized. Mitochondrial function was quantified by measurement of fuel oxidation rates in isolated hepatocytes and mitochondria. In addition, activities of mitochondrial and extramitochondrial enzymes were determined in isolat...

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Coenzyme A Metabolism in Vitamin B-12—Deficient Rats

Cited by 38 publications

References 35 publications

N-Lysine Propionylation Controls the Activity of Propionyl-CoA Synthetase

N-Lysine Propionylation Controls the Activity of Propionyl-CoA Synthetase

Abnormal Increase in the Expression Level of Proliferating Cell Nuclear Antigen (PCNA) in the Liver and Hepatic Injury in Rats with Dietary Cobalamin Deficiency

Increased hepatic mitochondrial capacity in rats with hydroxy-cobalamin[c-lactam]-induced methylmalonic aciduria.

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