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MetaCyc Pathway: L-lysine degradation XI (mammalian)
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: L-lysine degradation XI (mammalian)

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-lysine Degradation

Some taxa known to possess this pathway include : Bos taurus, Homo sapiens, Mus musculus, Rattus norvegicus

Expected Taxonomic Range: Eukaryota


L-lysine is an essential amino acid in humans. It is required for protein synthesis, enzyme catalysis, and L-carnitine biosynthesis. The first two steps of this lysine catabolic pathway mirror the terminal steps of lysine biosynthesis in lower eukaryotes. L-lysine is converted to L-saccharopine in the first step, and this pathway is also referred to as the saccharopine pathway. In higher eukaryotes, this mitochondrial pathway is the primary pathway for lysine catabolism in most tissues. L-lysine may also be catabolized via L-pipecolate in an alternate pathway in some tissues [Struys10].

About this Pathway

The first two reactions are catalyzed by bifunctional α-aminoadipic semialdehyde synthase, mitochondrial which possesses both lysine-ketoglutarate reductase and saccharopine dehydrogenase activities [Sacksteder00]. The nitrogen atom of (S)-2-amino-6-oxohexanoate is derived from the ε amino group of L-lysine. In the next step of the pathway, (S)-2-amino-6-oxohexanoate is converted to L-2-aminoadipate by α-aminoadipic semialdehyde dehydrogenase [Mills06]. The enzyme kynurenine/alpha-aminoadipate aminotransferase then transaminates L-2-aminoadipate to 2-oxoadipate [Goh02].

Mitochondrial probable 2-oxoglutarate dehydrogenase E1 component DHKTD1 is one of two known isoforms of the E1 subunit of the 2-ketoglutarate dehydrogenase complex. The 2-ketoglutarate dehydrogenase complex catalyzes the decarboxylation of 2-oxoglutarate to succinyl-CoA within the TCA cycle III (animals) [Reed01]. The probable 2-oxoglutarate dehydrogenase E1 component DHKTD1 may mediate the decarboxylation of 2-oxoadipate to glutaryl-CoA in the last step of this pathway [Danhauser12].

Superpathways: superpathway of L-lysine degradation

Variants: L-lysine degradation I, L-lysine degradation II (L-pipecolate pathway), L-lysine degradation III, L-lysine degradation IV, L-lysine degradation V, L-lysine degradation VI, L-lysine degradation VII, L-lysine degradation VIII, L-lysine degradation IX, L-lysine degradation X, L-lysine fermentation to acetate and butanoate

Revised 23-Oct-2013 by Weerasinghe D, SRI International


Broquist91: Broquist HP (1991). "Lysine-pipecolic acid metabolic relationships in microbes and mammals." Annu Rev Nutr 11;435-48. PMID: 1909881

Danhauser12: Danhauser K, Sauer SW, Haack TB, Wieland T, Staufner C, Graf E, Zschocke J, Strom TM, Traub T, Okun JG, Meitinger T, Hoffmann GF, Prokisch H, Kolker S (2012). "DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria." Am J Hum Genet 91(6);1082-7. PMID: 23141293

Goh02: Goh DL, Patel A, Thomas GH, Salomons GS, Schor DS, Jakobs C, Geraghty MT (2002). "Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT)." Mol Genet Metab 76(3);172-80. PMID: 12126930

Mills06: Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT (2006). "Mutations in antiquitin in individuals with pyridoxine-dependent seizures." Nat Med 12(3);307-9. PMID: 16491085

Reed01: Reed LJ (2001). "A trail of research from lipoic acid to alpha-keto acid dehydrogenase complexes." J Biol Chem 276(42);38329-36. PMID: 11477096

Sacksteder00: Sacksteder KA, Biery BJ, Morrell JC, Goodman BK, Geisbrecht BV, Cox RP, Gould SJ, Geraghty MT (2000). "Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia." Am J Hum Genet 66(6);1736-43. PMID: 10775527

Struys10: Struys EA, Jakobs C (2010). "Metabolism of lysine in alpha-aminoadipic semialdehyde dehydrogenase-deficient fibroblasts: evidence for an alternative pathway of pipecolic acid formation." FEBS Lett 584(1);181-6. PMID: 19932104

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

Blemings94: Blemings KP, Crenshaw TD, Swick RW, Benevenga NJ (1994). "Lysine-alpha-ketoglutarate reductase and saccharopine dehydrogenase are located only in the mitochondrial matrix in rat liver." J Nutr 124(8);1215-21. PMID: 8064371

Brocker10: Brocker C, Lassen N, Estey T, Pappa A, Cantore M, Orlova VV, Chavakis T, Kavanagh KL, Oppermann U, Vasiliou V (2010). "Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress." J Biol Chem 285(24);18452-63. PMID: 20207735

Fjellstedt75: Fjellstedt TA, Robinson JC (1975). "Purification and properties of L-lysine-alpha-ketoglutarate reductase from human placenta." Arch Biochem Biophys 168(2);536-48. PMID: 1169916

Han08: Han Q, Robinson H, Li J (2008). "Crystal structure of human kynurenine aminotransferase II." J Biol Chem 283(6);3567-73. PMID: 18056995

Hutzler75: Hutzler J, Dancis J (1975). "Lysine-ketoglutarate reductase in human tissues." Biochim Biophys Acta 377(1);42-51. PMID: 235294

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Marchitti08: Marchitti SA, Brocker C, Stagos D, Vasiliou V (2008). "Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily." Expert Opin Drug Metab Toxicol 4(6);697-720. PMID: 18611112

Markovitz84: Markovitz PJ, Chuang DT, Cox RP (1984). "Familial hyperlysinemias. Purification and characterization of the bifunctional aminoadipic semialdehyde synthase with lysine-ketoglutarate reductase and saccharopine dehydrogenase activities." J Biol Chem 259(19);11643-6. PMID: 6434529

Markovitz87: Markovitz PJ, Chuang DT (1987). "The bifunctional aminoadipic semialdehyde synthase in lysine degradation. Separation of reductase and dehydrogenase domains by limited proteolysis and column chromatography." J Biol Chem 262(19);9353-8. PMID: 3110158

Miyazaki04: Miyazaki T, Miyazaki J, Yamane H, Nishiyama M (2004). "alpha-Aminoadipate aminotransferase from an extremely thermophilic bacterium, Thermus thermophilus." Microbiology 150(Pt 7);2327-34. PMID: 15256574

Noda78: Noda C, Ichihara A (1978). "Purification and properties of L-lysine-alpha-ketoglutarate reductase from rat liver mitochondria." Biochim Biophys Acta 525(2);307-13. PMID: 687635

Okuno93: Okuno E, Tsujimoto M, Nakamura M, Kido R (1993). "2-Aminoadipate-2-oxoglutarate aminotransferase isoenzymes in human liver: a plausible physiological role in lysine and tryptophan metabolism." Enzyme Protein 47(3);136-48. PMID: 8087205

Papes99: Papes F, Kemper EL, Cord-Neto G, Langone F, Arruda P (1999). "Lysine degradation through the saccharopine pathway in mammals: involvement of both bifunctional and monofunctional lysine-degrading enzymes in mouse." Biochem J 344 Pt 2;555-63. PMID: 10567240

Rossi08: Rossi F, Garavaglia S, Montalbano V, Walsh MA, Rizzi M (2008). "Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia." J Biol Chem 283(6);3559-66. PMID: 18056996

Rubio06: Rubio S, Larson TR, Gonzalez-Guzman M, Alejandro S, Graham IA, Serrano R, Rodriguez PL (2006). "An Arabidopsis mutant impaired in coenzyme A biosynthesis is sugar dependent for seedling establishment." Plant Physiol 140(3);830-43. PMID: 16415216

Skvorak97: Skvorak AB, Robertson NG, Yin Y, Weremowicz S, Her H, Bieber FR, Beisel KW, Lynch ED, Beier DR, Morton CC (1997). "An ancient conserved gene expressed in the human inner ear: identification, expression analysis, and chromosomal mapping of human and mouse antiquitin (ATQ1)." Genomics 46(2);191-9. PMID: 9417906

Stockler: Stockler S, Plecko B, Gospe SM, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL "Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up." Mol Genet Metab 104(1-2);48-60. PMID: 21704546

Takeuchi83: Takeuchi F, Otsuka H, Shibata Y (1983). "Purification, characterization and identification of rat liver mitochondrial kynurenine aminotransferase with alpha-aminoadipate aminotransferase." Biochim Biophys Acta 743(3);323-30. PMID: 6830814

Tobes77: Tobes MC, Mason M (1977). "Alpha-Aminoadipate aminotransferase and kynurenine aminotransferase. Purification, characterization, and further evidence for identity." J Biol Chem 252(13);4591-9. PMID: 873907

Yu06a: Yu P, Li Z, Zhang L, Tagle DA, Cai T (2006). "Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family." Gene 365;111-8. PMID: 16376499

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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
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