Leucine degradation

Figure 9-4. Metabolism of the branched-chain amino acids. The first two reactions, transamination and oxidative decarboxylation, are catalyzed by the same enzyme in all cases. Details are provided only for isoleucine. Further metabolism of isoleucine and valine follows a common pathway to propionyl CoA. Subsequent steps in the leucine degradative pathway diverge to yield acetoacetate. An intermediate in the pathway is 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), which is a precursor for cytosolic cholesterol biosynthesis.

An alternative pathway of leucine degradation in the liver is oxidative decarboxylation by a cytosolic oxygenase to form a-hydroxyisovalerate.362... 

The catabolism of valine in heterotrophs follows an analogous series of reactions to those in leucine degradation through reaction 3. At this point the reactions proceed as follow from methylacrylyl-CoA ... 

Fig. 6.1. The L-leucine degradative pathway. Reactions for which inherited metabolic disorders have not been conclusively identified include A, leucine-isoleucine aminotransferase and the majority of the 3-methylglutaconic acidurias (6.6-6.7). 6.1, Branched-chain a-ketoacid dehydrogenase (BCKD) complex, a reaction also occurring in the initial steps of L-isoleucine and L-valine degradation 6.2, isovaleryl-CoA dehydrogenase 6.3, 3-methylcrotonyl-CoA carboxylase 6.4, 3-methylglutaconyl-CoA hydra-tase 6.8, HMG-CoA lyase. Pathologic urinary metabolites used as specific markers in the differential diagnosis are presented in squares. Abbreviation Co A, coenzyme A...

P-Methylcrotonyl-CoA carboxylase, which transforms p-methylcrotonyl-CoA into P-methylglutaconyl-CoA (Eq. 6), is a key enzyme in leucine degradation (47) ... 

Branched-chain amino acids as precursurs of plant isoprenoids L-Leucine and L-valine, when fed to germinating pea seeds (Pisum sativum) were incorporated into squalene and 6-amyrin [39]. Chemical degradation by ozonolysis of the radioactive squalene revealed an equal distribution of the radioactivity in the IPP-derived (4 portions per molecule) and the DMAPP-derived moieties (2 portions per molecule). However, an unbalanced distribution in favor of the DMAPP-derived moiety of monoterpenoids was found after feeding radioisotopically labeled L-leucine, L-valine, DL-alanine, acetate, and R,S-MVA to intact plants of Cinnamomum camphora and of Pelargonium roseum [40]. The relatively low incorporation of amino acids was explained by several hypotheses a) the radioactivity of amino acids is scattered into other metabolites rather than monoterpenoids b) there is a great pool of the amino acids which leads to dilution of radioactivity, and c) the low permeation of the amino acids into the biosynthetic site of monoterpenoids [40]. The DMAPP-derived moiety of monoterpenoids, biosynthesized from [U- C]leucine and [U- ]valine was labeled with more than 64% of the incorporated tracers, while this moiety when derived from [2- " C]MVA contained less than 32% of the tracers [40]. This lends support to the interpretation that both amino acids are incorporated not via MV A, but by an alternate route, e,g, a combination of the well known mammalian leucine degradation pathway and a reversal of the MVA shunt (see below). The distribution pattern in monoterpenoids after administration of [2- ]alanine was similar to that after incorporation of MVA, which indicates that alanine is first metabolized to acetyl-CoA, which then constructs preferentially the IPP-derived moiety of the monoterpenoids via MVA [40]. 

Figure 3. Appearance of phosphoenolpyruvate carboxykinase in developing rat liver, (a) The activity increase is expressed as units of enzyme per total liver, (b) Enzyme synthesis ( ) is expressed as the percent of radioactivity in the enzyme pool as compared to radioactivity in cytosol protein after injections of radioactive leucine. Degradation (o), in the same terms, is shown at various times after a leucine chase was given. The half-lives at each age are indicated. Details are given by Philippidis et al. (1972). Values are means SEM. T, term.

Stokke, O., Eldjarn, L., Jellum, E., Pande, H, and Waaler, P.E. (1972), /3-Methyl-crotonyl CoA carboxylase deficiency A new metabolic error in leucine degradation. Pediatrics, 49,726. 

As with the 5-amino-4-phenyl-l,3-dioxane auxiliary47 53, the rert-leucine ester group has to be removed by oxidative degradation, in this case by a regioselective decarboxylation using fe/7-butyl hypochlorite. The expense of this auxiliary, coupled with its destruction, limits the practical value of this interesting procedure. 

Inherited defects in the enzymes of (3-oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, and fatty hver. Defects are known in long- and short-chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of acute fetty liver of pr nancy). 3-Ketoacyl-CoA thiolase and HMG-CoA lyase deficiency also affect the degradation of leucine, a ketogenic amino acid (Chapter 30). 

Methionine metabolism Cysteine metabolism Valine, leucine, and isoleucine degradation... 

Valine, leucine, and isoleucine biosynthesis Lysine biosynthesis Lysine degradation Arginine and proline metabolism Histidine metabolism Tyrosine metabolism Phenylalanine metabolism Tryptophan metabolism Phenylalanine, tyrosine, and tryptophan biosynthesis Urea cycle and metabolism of amino groups... 

A recent study, however, has shown that aminopeptidase activity is present on the surface of porcine buccal mucosa, and that various aminopeptidase inhibitors, including amastatin and sodium deoxycholate, reduce the mucosal surface degradation of the aminopeptidase substrate, leucine-enkephalin [149], Since the peptidases are present on the surface of the buccal mucosa, they may act as a significant barrier to the permeability of compounds which are substrates for the enzyme. In addition to proteolytic enzymes, there exist some esterases, oxidases, and reductases originating from buccal epithelial cells, as well as phosphatases and carbohydrases present in saliva [154], all of which may potentially be involved in the metabolism of topically applied compounds. 

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