Leucine, catabolism

Massey LK, RS Conrad, JR Sokatch (1974) Regulation of leucine catabolism in Pseudomonas putida. J Bacteriol 118 112-120. 

Pyruvate carboxylase, which participates in gluconeogenesis and lipogenesis Acetyl-CoA carboxylase, which participates in fatty acid biosynthesis Propionyl-CoA carboxylase, which participates in isoleucine catabolism 3-Methylcrotonyl-CoA carboxylase, which participates in leucine catabolism... 

Figure 11 The putative catabolic pathway of L-leucine and its implications for strain improvement. For a promising host strain, the pathway to be blocked is indicated with thick double lines and the pathways to be fortified are indicated with thick arrows. Abbreviations for enzymes participating in the L-leucine catabolism and the acylation of tylosin VDH, valine (branched-chain amino acid) dehydrogenase BCDFI, branched-chain a-keto acid dehydrogenase IVD (AcdH), isovaleryl-CoA dehydrogenase (acyl-CoA dehydrogenase) MCC, 3-methylcrotonyl-CoA carboxylase EH, enoyl-CoA hydratase AcyA, mac-rolide 3-O-acyltransferase AcyBl, macrolide 4"-(9-acyltransferase.

Individuals who are deficient in HMG-CoA lyase are unable to complete the metabolism of leucine. The increased urinary excretion of 3-hydroxy-3-methylglutaric acids is the primary biochemical criterion that distinguishes this particular enzymatic defect from other defects in enzymes of leucine catabolism that also result in metabolic acidosis and abnormal organic aciduria. There is also substantial urinary excretion of intermediates of leucine catabolism, such as 3-methylglutaconic acid, and their metabolites, including 3-hydroxy-isovaleric acid produced from isovaleric acid. 

Acosta PB, YanniceUi S Disorders of leucine catabolism, in Acosta PB,Yannicelli S (edsy. Nutrition Support Protocols the Ross Metabolic Formula System. 4th ed. Abbott Laboratories, Columbus, OH, 2001, pp. 103-122. 

Poston (1984) showed that, in isolated rat tissues, about 5% of the catabolic flux of leucine was by way of aminomutase action to yield /S-leucine, and then isobutyryl CoA, with the remainder provided by the more conventional a-transamination pathway leading to the formation of isovaleryl CoA. In patients suffering from vitamin B12 deficiency, there is an elevation of plasma /S-leucine, suggesting that the aminomutase may act to metabolize /S -leucine arising from intestinal bacteria, rather than as a pathway for leucine catabolism. 

Leucine catabolism also occurs by a second, minor pathway. The first step in this pathway is catalyzed by leucine aminomutase (Poston, 1984). Leucine ami-nomutasc is one of the three vitamin Bjj-requiring enzymes in mammalian tissues. 

Leucine and lysine are purely ketogenic amino adds. The catabolism of these amino acids does not yield intermediates of the Krebs cycle. It does not yield pyruvate. It does not produce compoimds that can result in the net synthesis of glucose. Leucine catabolism results in the production of a molecule of acetyl-CoA and a molecule of acetoacetate lysine breakdown produces acetoacetyl-CoA. 

Isovaleric acidemia (IVA) is a disorder of leucine catabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. Since the initial report 40 years ago, IVA has been the main focus of the work of Dr. Kay Tanaka, one of the pioneers and arguably most productive contributors to our current... 

Figure XIII. Leucine catabolism and formation of 3-methyl butanoates and 3-methyl butylesters in banana.

Hydroxy-3-methylglutaiyl-(HMG-CoA), also a product < leucine catabolism... 

In leucine catabolism (Scheme 62c), the first steps leading to isovaleryl-CoA 233, X = CoA, are similar to those in the catabolism of valine 179 and isoleucine 212. When samples of (2R)- and (2S)-[2- H Jisovaleric acid 233, X = OH, were fed to biotin-deficient rats, / -hydroxyisovalerate 235 was isolated and shown to have lost the 2-pro-R hydrogen (212), thus indicating that the dehydrogenation step 233 234 had occurred with loss of this hydrogen. The hydration step 234 235 proved to be nonstereospecific for... 

IVA was initially described in 1966 and became the first organic acidemia described. IVA is caused by a deficiency of the enzyme isovaleryl-CoA dehydrogenase, an enzyme important in leucine catabolism and also important in the transfer of electrons to the respiratory chain [7, 13]. The consequent accumulating metabolites include isovaleric add, isovalerylglydne, 3-hydroxyisovaleric acid, and isovalerylcamitine (C5) [7, 13] (Fig. 17.3). These are easily identified on urine organic acid analysis and acylcamitine profile. The excretion of isovalerylglydne and 3-hydroxyisovaleric acid is diagnostic. 

Scheme 41. Proposed mechanism of leucine catabolism to DMAPP [63]...

More precise information on the pathway of leucine catabolism was obtained from studies on the formation of ketone bodies in liver slices incubated with and C Mabeled leucine and isovaleric acid. In these experiments it was found that leucine-3-C yielded acetoacetate in which the label was virtually all contained in the methyl and methylene carbons, and to approximately the same extent in each of these. Only a trace of radioactivity was found in the carboxyl carbon. On incubation with leucine-4-Ci the label occurred solely in the carbonyl group. This suggested that the isopropyl group of the amino acid had been directly converted to acetone. The over-all conclusion was that the isopropyl group forms acetone, and carbons 2 and 3 of the amino acid yield a 2-car-bon fragment which can condense to acetoacetate. The acetoacetate formed from leucine-4-C was not symmetrically labeled, the isotope being present only in the carbonyl carbon. 

Nemecek-Marshall M, Wojciechowsld C, Wagner WP, Fall R (1999) Acetone formation in the vibrio family a new pathway for bacterial leucine catabolism. J Bacteriol 181 7493... 

The inborn errors of L-leucine catabolism present biochemically with branched-chain amino and/or organic aciduria [1]. These disorders include maple syrup disease (MSD branched-chain a-ketoacid dehydrogenase (BCKD) deficiency), isovaleric acidemia (isovaleryl-coenzyme A (CoA) dehydrogenase deficiency), isolated 3-methylcrotonyl-CoA carboxylase deficiency, the 3-methylglutaconic acidurias (3-methylglutaconyl-CoA hydratase deficiency, Barth syndrome, and other disorders in which the primary defect has not been demonstrated), and 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency). 

Fig. 6.2. Screening policy and the diagnostic flow chart in the differentiation of defects of L-leucine catabolism.

Coon and co-workers ttt-ltJia) discovered and crystallized an enzyme Itia) named hydroxylamine kinase that degrades ATP in the presence of bicarbonate and hydroxylamine. It was believed that adenylic acid and pyrophosphate were products of this reaction and it was considered that this enzyme participated in the carboxylation reaction in leucine catabolism by activating COi. Active CO was presumed to be adenyl-COj. Later this enzyme was found not to participate in the carboxylation reactions. More recently Kupiecki and Coon lt4b) established that hydroxylamine kinase is very probably identical with pyruvic kinase and fluoro kinase of Tietz and Ochoa (96). Interesting differences were found in the activation of the different enzyme functions by metal ions. Zn, but not Mg++, promoted hydroxylamine kinase activity, whereas Mg, but not Zn promoted iluorokinase and pyruvic kinase activity. 

Smit, B.A., Engels, W.J.M., and Wouters, J.T.M. (2004) Diversity of L-leucine catabolism in various microorganisms involved in dairy fermentations, and identification of the rate-controlling step in the formation of the potent flavour component 3-methylbutanal. Appl Microbiol Biotechnol 64, 396-402. 

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