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PubMed2004

Fatty acid production from amino acids and alpha-keto acids by Brevibacterium linens BL2.

Low concentrations of branched-chain fatty acids, such as isobutyric and isovaleric acids, develop during the ripening of hard cheeses and contribute to the beneficial flavor profile. Catabolism of amino acids, such as branched-chain amino acids, by bacteria via aminotransferase reactions and alpha-keto acids is one mechanism to generate these flavorful compounds; however, metabolism of alpha-keto acids to flavor-associated compounds is controversial. The objective of this study was to determine the ability of Brevibacterium linens BL2 to produce fatty acids from amino acids and alpha-keto acids and determine the occurrence of the likely genes in the draft genome sequence. BL2 catabolized amino acids to fatty acids only under carbohydrate starvation conditions. The primary fatty acid end products from leucine were isovaleric acid, acetic acid, and propionic acid. In contrast, logarithmic-phase cells of BL2 produced fatty acids from alpha-keto acids only. BL2 also converted alpha-keto acids to branched-chain fatty acids after carbohydrate starvation was achieved. At least 100 genes are potentially involved in five different metabolic pathways. The genome of B. linens ATCC 9174 contained these genes for production and degradation of fatty acids. These data indicate that brevibacteria have the ability to produce fatty acids from amino and alpha-keto acids and that carbon metabolism is important in regulating this event.

Amino Acids↗
PubMed1986

Inhibition of glycine oxidation by pyruvate, alpha-ketoglutarate, and branched-chain alpha-keto acids in rat liver mitochondria: presence of interaction between the glycine cleavage system and alpha-keto acid dehydrogenase complexes.

Pyruvate, alpha-ketoglutarate, and branched-chain alpha-keto acids which were transaminated products of valine, leucine, and isoleucine inhibited glycine decarboxylation by rat liver mitochondria. However, glycine synthesis (the reverse reaction of glycine decarboxylation) was stimulated by those alpha-keto acids with the concomitant decarboxylation of alpha-keto acid added in the absence of NADH. Both the decarboxylation and the synthesis of glycine by mitochondrial extract were affected similarly by alpha-ketoglutarate and branched-chain alpha-keto acids in the absence of pyridine nucleotide, but not by pyruvate. This failure of pyruvate to have an effect was due to the lack of pyruvate oxidation activity in the mitochondrial extract employed. It indicated that those alpha-keto acids exerted their effects by providing reducing equivalents to the glycine cleavage system, possibly through lipoamide dehydrogenase, a component shared by the glycine cleavage system and alpha-keto acid dehydrogenase complexes. On the decarboxylation of pyruvate, alpha-ketoglutarate, and branched-chain alpha-keto acids in intact mitochondria, those alpha-keto acids inhibited one another. In similar experiments with mitochondrial extract, decarboxylations of alpha-ketoglutarate and branched-chain alpha-keto acid were inhibited by branched-chain alpha-keto acid and alpha-ketoglutarate, respectively, but not by pyruvate. NADH was unlikely to account for the inhibition. We suggest that the lipoamide dehydrogenase component is an indistinguishable constituent among alpha-keto acid dehydrogenase complexes and the glycine cleavage system in mitochondria in nature, and that lipoamide dehydrogenase-mediated transfer of reducing equivalents might regulate alpha-keto acid oxidation as well as glycine oxidation.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1997

Synthesis of optically active amino acids from alpha-keto acids with Escherichia coli cells expressing heterologous genes.

We describe a simple method for enzymatic synthesis of L and D amino acids from alpha-keto acids with Escherichia coli cells which express heterologous genes. L-amino acids were produced with thermostable L-amino acid dehydrogenase and formate dehydrogenase (FDH) from alpha-keto acids and ammonium formate with only an intracellular pool of NAD+ for the regeneration of NADH. We constructed plasmids containing, in addition to the FDH gene, the genes for amino acid dehydrogenases, including i.e., leucine dehydrogenase, alanine dehydrogenase, and phenylalanine dehydrogenase. L-Leucine, L-valine, L-norvaline, L-methionine, L-phenylalanine, and L-tyrosine were synthesized with the recombinant E. coli cells with high chemical yields (> 80%) and high optical yields (up to 100% enantiomeric excess). Stereospecific conversion of various alpha-keto acids to D amino acids was also examined with recombinant E. coli cells containing a plasmid coding for the four heterologous genes of the thermostable enzymes D-amino acid aminotransferase, alanine racemase, L-alanine dehydrogenase, and FDH. Optically pure D enantiomers of glutamate and leucine were obtained.

Alanine Dehydrogenase↗
PubMed1991

Reversed-phase high-performance liquid chromatographic analysis of branched-chain keto acid hydrazone derivatives: optimization of techniques and application to branched-chain keto acid balance studies across the forearm.

A sensitive method of quantifying branched-chain keto acids in plasma and whole blood samples is described. It is based on the separation by ion-pair reversed-phase liquid chromatography of 2,4-dinitrophenylhydrazine derivatives with ultraviolet detection. The sample clean-up steps that are usually required for reversed-phase high-performance liquid chromatography are eliminated. A reduction in ketoisocaproate isomer formation is obtained by incubation of derivatives in ice. The method is reproducible (coefficient of variation 2%, n = 5, at the 200-pmol level) and the ultraviolet response is linearly related to branched-chain keto acid concentration. Recoveries are high (greater than 95%). Other keto acids do not co-elute with branched-chain keto acids. Because of its sensitivity and precision, this method can be proposed for whole blood branched-chain keto acid balance studies across organs.

Biological Transport↗
PubMed1982

Signal function of metabolism of neutral amino acids and 2-keto acids for initiation of insulin secretion.

2-Ketocaproate and 2-ketoisocaproate were equally potent insulin secretagogues. The insulin secretory potency of L-leucine was less than half of that of the keto acids and L-norleucine did not induce any insulin release by isolated islets and by the perfused pancreas from ob/ob mice. Rates of decarboxylation of 2-keto-[1-14C]isocaproate and of 2-keto-[1-14C]caproate were equally high. The finding is consistent with the view that enhanced production of reducing equivalents is necessary for initiation of insulin release. The rates of decarboxylation and transamination of L-[1-14C]leucine by isolated pancreatic islets were several times higher than the rates observed with L-[1-14C]norleucine. Thus, the high activity of the pancreatic islet branched-chain amino acid aminotransferase may be important for the recognition of L-leucine as an insulin secretagogue by pancreatic B-cells.

Animals↗
PubMed1983

The relationship between branched-chain amino acids and alpha-keto acids in blood in uremia.

Branched-chain alpha-keto acid (BCKA) supplements are used as a nitrogen-free source of branched-chain amino acids (BCAA) in patients with chronic renal failure. Their use is dependent on the freely reversible interconversion of BCKA and BCAA in muscle tissue. In a group of eight young adults on dialysis compared to 11 normal healthy adults, the ratios of the fasting plasma concentrations of leucine and isoleucine to their corresponding alpha-keto acids, alpha-keto isocaproic acid and alpha-keto-beta-methyl-eta-valeric acid, respectively, were significantly elevated. These ratios appear to be sensitive to changes in intracellular glutamate and pyruvate. The ratios increased in seven insulin-dependent diabetics following insulin withdrawal, a situation where intracellular glutamate is increased. The ratios decreased in six normal healthy adults in response to submaximal treadmill exercise, a situation where intracellular pyruvate is increased. The elevated BCAA/BCKA ratios in uremia could be a reflection of reduced peripheral glucose utilization. A consequence of this will be enhanced conversion of supplemented BCKA to their corresponding BCAA. The close association between muscle BCAA and glucose metabolism suggests that the timing of BCKA administration in relation to energy intake might prove important.

Adolescent↗
PubMed2005

Dissociation of branched-chain alpha-keto acid dehydrogenase kinase (BDK) from branched-chain alpha-keto acid dehydrogenase complex (BCKDC) by BDK inhibitors.

Branched-chain alpha-keto acid dehydrogenase kinase (BDK) phosphorylates and inactivates the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), which is the rate-limiting enzyme in the branched-chain amino acid catabolism. BDK has been believed to be bound to the BCKDC. However, recent our studies demonstrated that protein-protein interaction between BDK and BCKDC is one of the factors to regulate BDK activity. Furthermore, only the bound form of BDK appears to have its activity. In the present study, we examined effects of BDK inhibitors on the amount of BDK bound to the BCKDC using rat liver extracts. The bound form of BDK in the extracts of liver from low protein diet-fed rats was measured by an immunoprecipitation pull down assay with or without BDK inhibitors. Among the BDK inhibitors. alpha-ketoisocaproate, alpha-chloroisocaproate, and a-ketoisovalerate released the BDK from the complex. Furthermore, the releasing effect of these inhibitors on the BDK appeared to depend on their inhibition constants. On the other hand, clofibric acid and thiamine pyrophosphate had no effect on the protein-protein interaction between two enzymes. These results suggest that the dissociation of the BDK from the BCKDC is one of the mechanisms responsible for the action of some inhibitors to BDK.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1988

Assessment of effects of amino acids and branched chain keto acids on leucine oxidation in human lymphocytes.

Effects of amino acids and branched chain keto acids on leucine transamination and oxidation were assessed in peripheral human lymphocytes. Isoleucine (80-200 mumol/l) and valine (250-500 mumol/l) diminished transamination and oxidation of leucine up to 25%, glutamine (50-1000 mumol/l) up to 55%. alpha-Ketoisocaproic acid (KIC; 200 mumol/l) augmented the activity state of branched chain keto acid dehydrogenase by 40%. It is concluded that in peripheral human lymphocytes (1) isoleucine, valine and glutamine are physiological inhibitors of leucine catabolism, and (2) leucine can promote its own degradation via KIC.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2000

Interactions among the branched-chain amino acids and their effects on methionine utilization in growing pigs: effects on plasma amino- and keto-acid concentrations and branched-chain keto-acid dehydrogenase activity.

The present experiment was designed to elucidate the mechanism of the methionine-sparing effect of excess branched-chain amino acids (BCAA) reported in the previous paper (Langer & Fuller, 2000). Twelve growing gilts (30-35 kg) were prepared with arterial catheters. After recovery, they received for 7 d a semipurified diet with a balanced amino acid pattern. On the 7th day blood samples were taken before (16 h postabsorptive) and after the morning meal (4 h postprandial). The animals were then divided into three groups and received for a further 7 d a methionine-limiting diet (80% of requirement) (1) without any amino acid excess; (2) with excess leucine (50% over requirement); or (3) with excesses of all three BCAA (leucine, isoleucine, valine, each 50% over the requirement). On the 7th day blood samples were taken as in the first period, after which the animals were killed and liver and muscle samples taken. Plasma amino acid and branched-chain keto acid (BCKA) concentrations in the blood and branched-chain keto-acid dehydrogenase (BCKDH; EC 1.2.4.4) activity in liver and muscle homogenates were determined. Compared with those on the balanced diet, pigs fed on methionine-limiting diets had significantly lower (P < 0.05) plasma methionine concentrations in the postprandial but not in the postabsorptive state. There was no effect of either leucine or a mixture of all three BCAA fed in excess on plasma methionine concentrations. Excess dietary leucine reduced (P < 0.05) the plasma concentrations of isoleucine and valine in both the postprandial and postabsorptive states. Plasma concentrations of the BCKA reflected the changes in the corresponding amino acids. Basal BCKDH activity in the liver and total BCKDH activity in the biceps femoris muscle were significantly (P < 0.05) increased by excesses of leucine or all BCAA.

Amino Acids↗
PubMed2006

Chemical conversion of alpha-amino acids into alpha-keto acids by 4,5-epoxy-2-decenal.

The comparative formation of phenylalanine and phenylpyruvic acid in the reaction of 4,5-epoxy-2-decenal with phenylalanine was studied to determine whether epoyalkenals may also degrade amino acids without producing their decarboxylation. Both compounds were produced in the reaction to an extent that depended on the reaction pH, the amount of lipid oxidation product, and the reaction time and temperature. The optimum pH was 3 for producing both carbonyl derivatives, and the amount of both compounds increased linearly with the amount of epoxyalkenal present in the reaction mixture. In addition, phenylpyruvic acid was produced to a higher extent than phenylacetaldehyde at 37 degrees C. However, at 60 degrees C the degradation of phenylpyruvic acid was observed and phenylacetaldehyde was usually found to a higher extent than the alpha-keto acid in the overnight-incubated reaction mixtures. The degradation of phenylpyruvic acid produced benzaldehyde and phenylacetaldehyde. All these results suggest that epoxyalkenals can not only degrade amino acids by a Strecker-type mechanism but convert them into their corresponding alpha-keto acids. This new reaction may be an alternative chemical route for the formation in foods of alpha-keto acids, which can later participate in the generation of important amino acid-derived flavor compounds.

Acetaldehyde↗
PubMed2004

Effects of ornithine on neutrophil (PMN) free amino acid and alpha-keto acid profiles and immune functions in vitro.

The objective of this study was to determine the effects of ornithine on polymorphonuclear leucocyte (PMN) free amino- and alpha-keto acid profiles, superoxide anion (O2-) generation, hydrogen peroxide (H2O2) formation and released myeloperoxidase activity (MPO). Exogenous ornithine significantly increased PMN asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, alpha-ketoglutarate and pyruvate as intracellular ornithine increased. Concerning PMN immune function markers ornithine increased H2O2-generation and MPO activity while O2- -formation was decreased. We believe therefore that ornithine is important for affecting PMN "susceptible free amino- and alpha-keto acid pool" although the mechanisms are not yet clear. This may be one of the determinants in PMN nutrition considerably influencing and modulating PMN host defense capability.

Adult↗
PubMedDate not supplied

Influence of branched-chain amino acids and branched-chain keto acids on protein synthesis in isolated hepatocytes.

We investigated the effects of the branched-chain amino acids--valine, leucine and isoleucine--or their keto analogs, the branched-chain keto acids--alpha-ketoisovaleric acid, alpha-ketoisocaproic acid and alpha-keto-beta-methylvaleric acid--on protein synthesis and secretion by monolayers of rabbit hepatocytes incubated with [35S] methionine in pulse-chase and steady-state experiments. The branched-chain amino acids (2.0 mM or 1.0 mM), in the presence or absence of insulin (2 X 10(-4) IU per dish) and in both types of experiments, reduced the trichloroacetic acid-precipitable 35S-protein secreted into the medium. The branched-chain keto acids (2.0 mM or 1.0 mM) had a stimulatory effect on secreted trichloroacetic acid-precipitable 35S-protein which was observed only by the pulse-chase technique in the presence of insulin. Immunoaffinity chromatography of medium demonstrated a slight inhibition by branched-chain amino acids and a slight stimulation by branched-chain keto acids on secretion of 35S-albumin and no effect of either treatment on secretion of 35S-fibrinogen. ELISA analysis of total (i.e., 35S-labeled and unlabeled) secreted albumin revealed an inhibitory effect of the branched-chain amino acids in both pulse-chase and steady-state experiments, and a small stimulatory effect, in steady-state experiments, of the branched-chain keto acids; both effects were insulin-dependent. Total secreted fibrinogen, under steady-state conditions, was increased by the branched-chain keto acids in the presence of insulin, while transferrin production was unaffected by any treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids, Branched-Chain↗
PubMed1996

Inhibition of D-amino acid oxidase by alpha-keto acids analogs of amino acids.

The inhibition of D-amino acid oxidase by certain alpha-keto acids products of the reaction with D-amino acids, in particular alpha-keto acids that are analogs of the amino acids alanine, valine, leucine, phenylanaline, phenylglycine, tyrosine and tryptophan, is reported. All the alpha-keto acids assayed behaved as substrate competitive inhibitors of the enzyme. The relationship between the degree of inhibition and the structure of the inhibitor is discussed.

Amino Acids↗
PubMed2000

Amino acid and alpha-keto acid metabolism depends on oxygen availability in chronic hemodialysis patients.

Amino acid and alpha-keto acid metabolism depends on oxygen availability in chronic hemodialysis patients. Malnutrition in hemodialysis (HD) patients with renal anemia is reflected in an abnormal plasma amino acid profile. We wished to determine the extent to which malnutrition can be improved by correcting anemia with recombinant human erythropoietin (rhEPO) and supplemental iron. As specific parameters we measured and compared the plasma concentrations of the branched-chain amino acids valine, leucine and isoleucine and their transamination products - major participants in proteolysis and protein biosynthesis - using HPLC with fluorescence detection in 45 severely anemic HD patients (group A: Hb 7.2 +/- 0.8 g/dl), 34 patients with partially corrected anemia (group B: Hb 10.3 +/- 0.6 g/dl) and 35 HD patients with totally corrected anemia (group C: Hb 13.5 +/- 0.7 g/dl). Sixty healthy subjects (group N: Hb 14.2 +/- 1.1 g/dl) served as controls. Correlating with the degree of correction (A/B/C/N), a significant shift to anabolic metabolism was observed in the plasma levels of valine: 130/146/155/205 micromol/l; leucine: 73/71/80/110 micromol/l and alpha-ketoisocaproate (KIC): 11.4/11.8/15.1/ 30.4 micromol/l. It is concluded that energy metabolism becomes increasingly anabolic as hemoglobin levels are normalized.

Amino Acids, Essential↗