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MetaCyc Pathway: L-leucine degradation I
Inferred from experiment

Enzyme View:

Pathway diagram: L-leucine degradation I

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Degradation/Utilization/AssimilationAmino Acids DegradationProteinogenic Amino Acids DegradationL-leucine Degradation

Some taxa known to possess this pathway include : Acer pseudoplatanus, Bacillus subtilis, Homo sapiens, Pseudomonas aeruginosa, Pseudomonas aeruginosa PAO1, Pseudomonas fluorescens, Pseudomonas mevalonii, Pseudomonas oleovorans, Pseudomonas putida, Streptomyces avermitilis

Expected Taxonomic Range: Bacteria , Eukaryota

L-leucine is one of the three main branched chain amino acids (BCAAs), along with L-isoleucine and L-valine. The catabolic pathways of the BCAAs can be divided into two sequential series of reactions, referred to as the common pathway and the distal pathway.

The common pathway includes the enzymes branched-chain-amino-acid aminotransferase, branched-chain α-keto acid dehydrogenase complex, and 2-methylacyl-CoA dehydrogenase. These three enzymes catalyze the conversion of all three BCAAs to their respective acyl-CoA derivatives ( methylacrylyl-CoA, 3-methylcrotonyl-CoA, and (E)-2-methylcrotonoyl-CoA for L-valine, L-leucine, and L-isoleucine, respectively), though the intermediates formed by these enzymes are different for the different amino acids. The distal parts of the pathways are completely different for the three BCAAs, and comprise enzymes specific for each amino acid [Massey76].

This Leucine degradation pathway is wide spread, and is found in microorganisms, higher plants, and animals, including mammals.

The catabolism of L-leucine begins with its transamination to 4-methyl-2-oxopentanoate, followed by oxidative decarboxylation to isovaleryl-CoA. isovaleryl-CoA then undergoes a four-step process, involving dehydrogenation to 3-methylcrotonyl-CoA, carboxylation to 3-methylglutaconyl-CoA, hydration to (S)-3-hydroxy-3-methylglutaryl-CoA, and finally a thioester hydrolysis forming acetyl-CoA and acetoacetate [Massey74]. Leucine degradation is different from the degradation of the other branched-chain amino acids, in that it includes a carboxylation step. The CO2 fixing enzyme, methylcrotonyl-CoA carboxylase, requires a biotin cofactor.

In adipocytes, unlike other tissues, leucine is a significant precursor for fatty acid and sterol biosynthesis, especially in the presence of glucose [Feller62]. Furthermore, leucine apparently serves as a source of nitrogen for synthesis of L-glutamine and, to lesser extents, L-glutamate and L-alanine, which are released by adipocytes [Tischler80] and can serve as substrates for gluconeogenesis in liver and kidney [Frerman83].

It should be mentioned that alternative leucine degradation pathways exist. In one such pathway, documented in Clostridium sporogenes, leucine is degraded to isobutanoate and acetate via (3R)-β-leucine (see L-leucine degradation II). Additional pathways which are currently not characterized very well include the conversion of leucine to acetone by members of the Vibrio family [NemecekMarshall99], and the catabolism of leucine to branched-chain fatty acids in Staphylococcus xylosus [Beck04].

A portion of this leucine degradation pathway also participates in the final phase of the acyclic terpene utilization pathway, beginning at 3-methylcrotonyl-CoA as shown in the pathway link from cis-genanyl-CoA degradation. The acyclic terpene utilization pathway includes pathways citronellol degradation, cis-genanyl-CoA degradation and this pathway, with its associated pathway link to acetoacetate degradation (to acetyl CoA). In species of Pseudomonas the enzymes of L-leucine/ isovalerate utilization are encoded in the liuRABCDE gene cluster (reviewed in [ForsterFromme10]).

Variants: L-leucine degradation II, L-leucine degradation III

Created 10-Mar-1999 by Wagg J, SRI International
Revised 06-Jan-2006 by Caspi R, SRI International
Revised 15-Dec-2010 by Fulcher CA, SRI International


Beck04: Beck HC, Hansen AM, Lauritsen FR (2004). "Catabolism of leucine to branched-chain fatty acids in Staphylococcus xylosus." J Appl Microbiol 96(5);1185-93. PMID: 15078537

Feller62: Feller, D.D., Feist, E. (1962). "The conversion of leucine carbon into CO2, fatty acids and other products by adipose tissue." Biochim Biophys Acta 62;40-4. PMID: 13892210

ForsterFromme10: Forster-Fromme K, Jendrossek D (2010). "Catabolism of citronellol and related acyclic terpenoids in pseudomonads." Appl Microbiol Biotechnol 87(3);859-69. PMID: 20490788

Frerman83: Frerman FE, Sabran JL, Taylor JL, Grossberg SE (1983). "Leucine catabolism during the differentiation of 3T3-L1 cells. Expression of a mitochondrial enzyme system." J Biol Chem 258(11);7087-93. PMID: 6304077

Massey74: Massey LK, Conrad RS, Sokatch JR (1974). "Regulation of leucine catabolism in Pseudomonas putida." J Bacteriol 118(1);112-20. PMID: 4150714

Massey76: Massey LK, Sokatch JR, Conrad RS (1976). "Branched-chain amino acid catabolism in bacteria." Bacteriol Rev 40(1);42-54. PMID: 773366

NemecekMarshall99: Nemecek-Marshall M, Wojciechowski C, Wagner WP, Fall R (1999). "Acetone formation in the Vibrio family: a new pathway for bacterial leucine catabolism." J Bacteriol 181(24);7493-9. PMID: 10601206

Tischler80: Tischler ME, Goldberg AL (1980). "Leucine degradation and release of glutamine and alanine by adipose tissue." J Biol Chem 255(17);8074-81. PMID: 6773935

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

AEvarsson00: AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG (2000). "Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease." Structure 8(3);277-91. PMID: 10745006

Aguilar06: Aguilar JA, Zavala AN, Diaz-Perez C, Cervantes C, Diaz-Perez AL, Campos-Garcia J (2006). "The atu and liu clusters are involved in the catabolic pathways for acyclic monoterpenes and leucine in Pseudomonas aeruginosa." Appl Environ Microbiol 72(3);2070-9. PMID: 16517656

Aguilar08: Aguilar JA, Diaz-Perez C, Diaz-Perez AL, Rodriguez-Zavala JS, Nikolau BJ, Campos-Garcia J (2008). "Substrate specificity of the 3-methylcrotonyl coenzyme A (CoA) and geranyl-CoA carboxylases from Pseudomonas aeruginosa." J Bacteriol 190(14);4888-93. PMID: 18469096

Anderson89b: Anderson DH, Rodwell VW (1989). "Nucleotide sequence and expression in Escherichia coli of the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene of Pseudomonas mevalonii." J Bacteriol 171(12);6468-72. PMID: 2687236

Ashmarina94: Ashmarina LI, Rusnak N, Miziorko HM, Mitchell GA (1994). "3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes." J Biol Chem 269(50);31929-32. PMID: 7527399

Aubert96: Aubert S, Alban C, Bligny R, Douce R (1996). "Induction of beta-methylcrotonyl-coenzyme A carboxylase in higher plant cells during carbohydrate starvation: evidence for a role of MCCase in leucine catabolism." FEBS Lett 383(3);175-80. PMID: 8925891

Bachhawat55: Bachhawat, B.K., Robinson, W.G., Coon, M.J. (1955). "The enzymatic cleavage of beta-hydroxy-beta-methylglutaryl coenzyme A to acetoacetate and acetyl coenzyme A." J Biol Chem 216(2);727-36. PMID: 13271348

Battaile04: Battaile KP, Nguyen TV, Vockley J, Kim JJ (2004). "Structures of isobutyryl-CoA dehydrogenase and enzyme-product complex: comparison with isovaleryl- and short-chain acyl-CoA dehydrogenases." J Biol Chem 279(16);16526-34. PMID: 14752098

Beach89: Beach MJ, Rodwell VW (1989). "Cloning, sequencing, and overexpression of mvaA, which encodes Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase." J Bacteriol 171(6);2994-3001. PMID: 2656635

Brown02a: Brown RM, Head RA, Brown GK (2002). "Pyruvate dehydrogenase E3 binding protein deficiency." Hum Genet 110(2);187-91. PMID: 11935326

Chang02: Chang CF, Chou HT, Chuang JL, Chuang DT, Huang TH (2002). "Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex." J Biol Chem 277(18);15865-73. PMID: 11839747

Chang06: Chang CF, Chou HT, Lin YJ, Lee SJ, Chuang JL, Chuang DT, Huang TH (2006). "Structure of the subunit binding domain and dynamics of the di-domain region from the core of human branched chain alpha-ketoacid dehydrogenase complex." J Biol Chem 281(38);28345-53. PMID: 16861235

ChavezAviles09: Chavez-Aviles M, Diaz-Perez AL, Reyes-de la Cruz H, Campos-Garcia J (2009). "The Pseudomonas aeruginosa liuE gene encodes the 3-hydroxy-3-methylglutaryl coenzyme A lyase, involved in leucine and acyclic terpene catabolism." FEMS Microbiol Lett 296(1);117-23. PMID: 19459965

ChavezAviles10: Chavez-Aviles M, Diaz-Perez AL, Campos-Garcia J (2010). "The bifunctional role of LiuE from Pseudomonas aeruginosa, displays additionally HIHG-CoA lyase enzymatic activity." Mol Biol Rep 37(4);1787-91. PMID: 19597963

Chen94a: Chen D, Swenson RP (1994). "Cloning, sequence analysis, and expression of the genes encoding the two subunits of the methylotrophic bacterium W3A1 electron transfer flavoprotein." J Biol Chem 269(51);32120-30. PMID: 7798207

Chuang90: Chuang JL, Cox RP, Chuang DT (1990). "Molecular cloning of the mature E1b-beta subunit of human branched-chain alpha-keto acid dehydrogenase complex." FEBS Lett 262(2);305-9. PMID: 2335211

Chuang94: Chuang JL, Fisher CR, Cox RP, Chuang DT (1994). "Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex." Am J Hum Genet 55(2);297-304. PMID: 8037208

Chuang95: Chuang JL, Davie JR, Chinsky JM, Wynn RM, Cox RP, Chuang DT (1995). "Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1 alpha locus of Hispanic-Mexican patients." J Clin Invest 95(3);954-63. PMID: 7883996

Chuang96: Chuang JL, Cox RP, Chuang DT (1996). "Maple syrup urine disease: the E1beta gene of human branched-chain alpha-ketoacid dehydrogenase complex has 11 rather than 10 exons, and the 3' UTR in one of the two E1beta mRNAs arises from intronic sequences." Am J Hum Genet 58(6);1373-7. PMID: 8651316

Collier72: Collier RH, Kohlhaw G (1972). "Nonidentity of the aspartate and the aromatic aminotransferase components of transaminase A in Escherichia coli." J Bacteriol 1972;112(1);365-71. PMID: 4404056

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Wed Jan 2, 2002, biocyc12.