Alpha-aminoadipic semialdehyde synthase explained

Alpha-aminoadipic semialdehyde synthase is an enzyme encoded by the AASS gene in humans and is involved in their major lysine degradation pathway. It is similar to the separate enzymes coded for by the LYS1 and LYS9 genes in yeast, and related to, although not similar in structure, the bifunctional enzyme found in plants.[1] In humans, mutations in the AASS gene, and the corresponding alpha-aminoadipic semialdehyde synthase enzyme are associated with familial hyperlysinemia.[2] [3] [4] This rare disease is inherited in an autosomal recessive pattern and patients often have no clinical symptoms.

Function

The alpha-aminoadipic semialdehyde synthase protein catalyzes the first two steps in the mammalian L-lysine degradation via saccharopine pathway within the mitochondria, which is thought to be the main metabolic route for lysine degradation in upper eukaryotes.[5] [6] The specific subpathway that this enzyme focuses on is the synthesis of glutaryl-CoA from L-lysine.[7] Glutaryl-CoA can act as an intermediate in a more expanded conversion/degradation pathway from L-lysine to acetyl-CoA.

Two noticeable components of the L-lysine degradation via saccharopine pathway are the intermediately-used reaction/product glutamate and the eventual carbon sink acetyl-CoA. Glutamate is an important compound within the body which acts as a neurotransmitter tied to learning and Huntington's disease.[8] [9] Acetyl-CoA is arguably of an even higher level of importance, acting as one of the integral components of the Citric Acid/Kreb cycle, with the primary function of delivering an acetyl group to be oxidized for energy production.[10] Thus, the function of alpha-aminoadipic semialdehyde synthase is tied to the levels of two integral compounds within the body.

Mechanism

First, the N-terminal portion of this enzyme which contains lysine-ketoglutarate reductase (LOR/LKR) activity (EC:1.5.1.8) condenses lysine and 2-oxoglutarate to a molecule called saccharopine (Reaction 1 on the figure to the right). Then, the C-terminal portion of this enzyme, which contains saccharopine dehydrogenase (SHD) activity (EC:1.5.1.9), catalyzes the oxidation of saccharopine to produce alpha-aminoadipic semialdehyde and glutamate (Reaction 2 on the figure to the right). Note: These reactions are the reverse of the corresponding steps in the lysine biosynthesis pathways present in yeast and fungi.[11] [12] [13]

These reactions can be visualized as well in reaction equation form:

N(6)-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O = L-lysine + 2-oxoglutarate + NADPH followed by

N(6)-(L-1,3-dicarboxypropyl)-L-lysine + NAD+ + H2O = L-glutamate + (S)-2-amino-6-oxohexanoate + NADH.

Structure

The native human enzyme is bifunctional, much like the LKR/SHD found in plants, and thus, is thought to be similar in structure. The bifunctionality of this enzyme comes from the fact that it contains two distinct active sites, one at its C-terminal, and one at its N-terminal. The C-terminal portion of alpha-aminoadipic semialdehyde synthase contains the SHD activity and the N-terminal portion contains LKR. To date, a structure of alpha-aminoadipic semialdehyde synthase has not been determined.[14] The enzyme does not have linker region present in plants between its C and N-termini, so theories suggest the actual structure contains an LKR-activity region bound to an SHD-activity region, like that in Magnaporthe grisea.[15]

Disease relevance

Alpha-aminoadipic semialdehyde synthase is encoded for by the AASS gene, and mutations in this gene lead to hyperlysinemia. This is characterized by impaired breakdown of lysine which results in elevated levels of lysine in the blood and urine. These increased levels of lysine do not appear to have any negative effects on the body. Other names for this condition include:

Hyperlysinemia is characterized by elevated plasma lysine levels that exceed 600 μmol/L and can reach up to 2000 μmol/L.[16] [17] These increased levels of lysine do not appear to have any negative effects on the body. The main reason for this is that several alternative biochemical reactions can take place. First, lysine can be used in place of ornithine in the urea cycle resulting in the production of homoarginine.[18] Additionally, even though most mammals use the saccharopine pathway for most lysine degradation (Path 1), the brain has an alternative pathway (Path 2) which goes through an L-pipecolic acid intermediate - both of these can be seen in the figure. It is important to note that Path 1 takes place in the mitochondria while Path 2 takes places in the peroxisome. Looking at other key enzymes within the L-lysine degradation pathway, ALDH7A1 is deficient in children with pyridoxine-dependent seizures.[19] GCDH is deficient in glutaric aciduria type 1.[20] The intermediate 2-oxoadipate is metabolized by 2-oxoadipate dehydrogenase, resembling the Citric Acid/Kreb cycle enzyme complex 2-oxoglutarate dehydrogenase.

Two types of familial hyperlysinemia have been described so far: type I is associated with a combined deficiency of the two enzyme activities, LOR and SDH, whereas in familial hyperlysinemia type II only the saccharopine dehydrogenase activity is impaired.[21] [22] Type II hyperlysinemia is also referred to as saccharopinuria.[23]

An additional condition shown to be related to hyperlysinemia is dienoyl-CoA reductase deficiency, though this is a relatively recent discovery and there are not many publications supporting this.[24]

Further reading

Notes and References

  1. Zhu X, Tang G, Galili G . The activity of the Arabidopsis bifunctional lysine-ketoglutarate reductase/saccharopine dehydrogenase enzyme of lysine catabolism is regulated by functional interaction between its two enzyme domains . The Journal of Biological Chemistry . 277 . 51 . 49655–61 . December 2002 . 12393892 . 10.1074/jbc.M205466200 . free .
  2. Sacksteder KA, Biery BJ, Morrell JC, Goodman BK, Geisbrecht BV, Cox RP, Gould SJ, Geraghty MT . Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia . American Journal of Human Genetics . 66 . 6 . 1736–43 . June 2000 . 10775527 . 1378037 . 10.1086/302919 .
  3. Web site: Entrez Gene: AASS aminoadipate-semialdehyde synthase.
  4. Web site: hyperlysinemia . Genetics Home Reference . 2017-03-04 .
  5. Papes F, Kemper EL, Cord-Neto G, Langone F, Arruda P . Lysine degradation through the saccharopine pathway in mammals: involvement of both bifunctional and monofunctional lysine-degrading enzymes in mouse . The Biochemical Journal . 344 . 2 . 555–63 . December 1999 . 10567240 . 1220675 . 10.1042/0264-6021:3440555 .
  6. 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, Kölker S . DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria . American Journal of Human Genetics . 91 . 6 . 1082–7 . December 2012 . 23141293 . 3516599 . 10.1016/j.ajhg.2012.10.006 .
  7. Web site: Alpha-aminoadipic semialdehyde synthase, mitochondrial . . 2017-03-04 .
  8. Meldrum BS . Glutamate as a neurotransmitter in the brain: review of physiology and pathology . The Journal of Nutrition . 130 . 4S Suppl . 1007S–15S . April 2000 . 10736372 . 10.1093/jn/130.4.1007s . 2017-03-05 . https://web.archive.org/web/20170516224434/http://jn.nutrition.org/content/130/4/1007.long . 2017-05-16 . dead . free .
  9. Web site: About Glutamate Toxicity . Huntington’s Disease Society of America . Huniting Disease Outreach for Education at Stanford (HOPES) . 26 June 2011 . 2017-03-05 .
  10. Web site: Acetyl CoA Crossroads Compound . Virtual ChemBook . Elmhurst College . Ophardt CE . 2003 . 2017-03-05 . 2016-11-15 . https://web.archive.org/web/20161115202146/http://chemistry.elmhurst.edu/vchembook/623acetylCoAfate.html . dead .
  11. Markovitz PJ, Chuang DT, Cox RP . Familial hyperlysinemias. Purification and characterization of the bifunctional aminoadipic semialdehyde synthase with lysine-ketoglutarate reductase and saccharopine dehydrogenase activities . The Journal of Biological Chemistry . 259 . 19 . 11643–6 . October 1984 . 10.1016/S0021-9258(20)71252-4 . 6434529 . free .
  12. Jones EE, Broquist HP . Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis. Ii. studies in Saccharomyces . The Journal of Biological Chemistry . 240 . 2531–6 . June 1965 . 6 . 10.1016/S0021-9258(18)97358-8 . 14304864 . free .
  13. Trupin JS, Broquist HP . Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis. I. studies in neurospora crassa . The Journal of Biological Chemistry . 240 . 2524–30 . June 1965 . 6 . 10.1016/S0021-9258(18)97357-6 . 14304863 . free .
  14. Web site: RCSB Protein Data Bank. AASS - aminoadipate-semialdehyde synthase. PDB. 2017-03-06. 2017-11-07. https://web.archive.org/web/20171107010007/http://www.rcsb.org/pdb/gene/AASS?evtc=Suggest&evta=GeneView&evtl=autosearch_SearchBar_querySuggest. dead.
  15. Johansson E, Steffens JJ, Lindqvist Y, Schneider G . Crystal structure of saccharopine reductase from Magnaporthe grisea, an enzyme of the alpha-aminoadipate pathway of lysine biosynthesis . Structure . 8 . 10 . 1037–47 . October 2000 . 11080625 . 10.1016/s0969-2126(00)00512-8 . free .
  16. Book: Saudubray JM, van den Berghe G, Walter JH . Inborn metabolic diseases diagnosis and treatment . 2012 . Springer . Berlin . 978-3-642-15720-2 . 5th . Cerebral organic acid disorders and other disorders of lysine catabolism . Hoffmann GF, Kolker S . 333–346 .
  17. Saudubray JM, Rabier D . Biomarkers identified in inborn errors for lysine, arginine, and ornithine . The Journal of Nutrition . 137 . 6 Suppl 2 . 1669S–1672S . June 2007 . 10.1093/jn/137.6.1669S . 17513445 . free .
  18. vd Heiden C, Brink M, de Bree PK, v Sprang FJ, Wadman SK, de Pater JM, van Biervliet JP . Familial hyperlysinaemia due to L-lysine alpha-ketoglutarate reductase deficiency: results of attempted treatment . Journal of Inherited Metabolic Disease . 1 . 3 . 89–94 . 1978 . 116084 . 10.1007/bf01805679. 35326745 .
  19. Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT . Mutations in antiquitin in individuals with pyridoxine-dependent seizures . Nature Medicine . 12 . 3 . 307–9 . March 2006 . 16491085 . 10.1038/nm1366 . 27940375 .
  20. Goodman SI, Kratz LE, DiGiulio KA, Biery BJ, Goodman KE, Isaya G, Frerman FE . Cloning of glutaryl-CoA dehydrogenase cDNA, and expression of wild type and mutant enzymes in Escherichia coli . Human Molecular Genetics . 4 . 9 . 1493–8 . September 1995 . 8541831 . 10.1093/hmg/4.9.1493.
  21. Dancis J, Hutzler J, Cox RP . Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on terminology . American Journal of Human Genetics . 31 . 3 . 290–9 . May 1979 . 463877 . 1685795.
  22. Cederbaum SD, Shaw KN, Dancis J, Hutzler J, Blaskovics JC . Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria . The Journal of Pediatrics . 95 . 2 . 234–8 . August 1979 . 571908 . 10.1016/s0022-3476(79)80657-5.
  23. Houten SM, Te Brinke H, Denis S, Ruiter JP, Knegt AC, de Klerk JB, Augoustides-Savvopoulou P, Häberle J, Baumgartner MR, Coşkun T, Zschocke J, Sass JO, Poll-The BT, Wanders RJ, Duran M . Genetic basis of hyperlysinemia . Orphanet Journal of Rare Diseases . 8 . 57 . April 2013 . 23570448 . 10.1186/1750-1172-8-57 . 3626681 . free .
  24. Houten SM, Denis S, Te Brinke H, Jongejan A, van Kampen AH, Bradley EJ, Baas F, Hennekam RC, Millington DS, Young SP, Frazier DM, Gucsavas-Calikoglu M, Wanders RJ . Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia . Human Molecular Genetics . 23 . 18 . 5009–16 . September 2014 . 24847004 . 10.1093/hmg/ddu218 . free .

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