Alpha-aminoadipic semialdehyde synthase

Last updated
AASS
Identifiers
Aliases AASS , LKR/SDH, LKRSDH, LORSDH, aminoadipate-semialdehyde synthase
External IDs OMIM: 605113 MGI: 1353573 HomoloGene: 4212 GeneCards: AASS
Orthologs
SpeciesHumanMouse
Entrez

10157

30956

Ensembl

ENSG00000008311

ENSMUSG00000029695

UniProt

Q9UDR5

Q99K67

RefSeq (mRNA)

NM_005763

NM_013930

RefSeq (protein)

NP_005754

NP_038958

Location (UCSC) Chr 7: 122.06 – 122.14 Mb Chr 6: 23.07 – 23.13 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] In humans, mutations in the AASS gene, and the corresponding alpha-aminoadipic semialdehyde synthase enzyme are associated with familial hyperlysinemia. [5] [7] [8] This rare disease is inherited in an autosomal recessive pattern and patients often have no clinical symptoms. [9]

Contents

Function

Pathways for L-Lysine Degradation in Mammalian Systems.png

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. [11] [12] The specific subpathway that this enzyme focuses on is the synthesis of glutaryl-CoA from L-lysine. [9] 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. [13] [14] 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. [15] Thus, the function of alpha-aminoadipic semialdehyde synthase is tied to the levels of two integral compounds within the body.

Mechanism

Lysine Degradation Steps Catalyzed by Alpha-aminoadipic semialdehyde dehydrogenase Lysine Degradation Steps Catalyzed by Alpha-aminoadipic semialdehyde dehydrogenase.png
Lysine Degradation Steps Catalyzed by Alpha-aminoadipic semialdehyde dehydrogenase

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). [7] [11] 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). [7] [11] Note: These reactions are the reverse of the corresponding steps in the lysine biosynthesis pathways present in yeast and fungi. [16] [17] [18]

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. [9]

Structure

The native human enzyme is bifunctional, much like the LKR/SHD found in plants, and thus, is thought to be similar in structure. [16] 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. [7] The C-terminal portion of alpha-aminoadipic semialdehyde synthase contains the SHD activity and the N-terminal portion contains LKR. [19] To date, a structure of alpha-aminoadipic semialdehyde synthase has not been determined. [20] 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 . [19]

Crystal structure of saccharopine reductase from Magnaporthe grisea Magnaporthe grisea SHD 2.png
Crystal structure of saccharopine reductase from Magnaporthe grisea

Disease relevance

Alpha-aminoadipic semialdehyde synthase is encoded for by the AASS gene, and mutations in this gene lead to hyperlysinemia. [5] [7] 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. [8] Other names for this condition include: [8]

Hyperlysinemia is characterized by elevated plasma lysine levels that exceed 600 μmol/L and can reach up to 2000 μmol/L. [21] [22] These increased levels of lysine do not appear to have any negative effects on the body. [8] 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. [23] 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. [23] It is important to note that Path 1 takes place in the mitochondria while Path 2 takes places in the peroxisome. [12] Looking at other key enzymes within the L-lysine degradation pathway, ALDH7A1 is deficient in children with pyridoxine-dependent seizures. [24] GCDH is deficient in glutaric aciduria type 1. [25] The intermediate 2-oxoadipate is metabolized by 2-oxoadipate dehydrogenase, resembling the Citric Acid/Kreb cycle enzyme complex 2-oxoglutarate dehydrogenase. [10]

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. [26] [27] Type II hyperlysinemia is also referred to as saccharopinuria. [10]

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. [28]

Related Research Articles

<span class="mw-page-title-main">Citric acid cycle</span> Series of interconnected biochemical reactions

The citric acid cycle —also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

<span class="mw-page-title-main">Lysine</span> Amino acid

Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated −NH+
3 form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain lysyl ((CH2)4NH2), classifying it as a basic, charged (at physiological pH), aliphatic amino acid. It is encoded by the codons AAA and AAG. Like almost all other amino acids, the α-carbon is chiral and lysine may refer to either enantiomer or a racemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomer L-lysine, where the α-carbon is in the S configuration.

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Homoserine</span> Chemical compound

Homoserine (also called isothreonine) is an α-amino acid with the chemical formula HO2CCH(NH2)CH2CH2OH. L-Homoserine is not one of the common amino acids encoded by DNA. It differs from the proteinogenic amino acid serine by insertion of an additional -CH2- unit into the backbone. Homoserine, or its lactone form, is the product of a cyanogen bromide cleavage of a peptide by degradation of methionine.

<span class="mw-page-title-main">Saccharopinuria</span> Medical condition

Saccharopinuria, also called saccharopinemia, saccharopine dehydrogenase deficiency or alpha-aminoadipic semialdehyde synthase deficiency, is a variant form of hyperlysinemia. It is caused by a partial deficiency of the enzyme saccharopine dehydrogenase, which plays a secondary role in the lysine metabolic pathway. Inheritance is thought to be autosomal recessive, but this cannot be established as individuals affected by saccharopinuria typically have only a 40% reduction in functional enzyme.

<span class="mw-page-title-main">Hyperlysinemia</span> Medical condition

Hyperlysinemia is an autosomal recessive metabolic disorder characterized by an abnormal increase of lysine in the blood, but appears to be benign. It is caused by mutations in AASS, which encodes α-aminoadipic semialdehyde synthase.

<span class="mw-page-title-main">Succinic semialdehyde dehydrogenase deficiency</span> Rare disorder involving deficiency in GABA degradation

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids).

<span class="mw-page-title-main">1-Pyrroline-5-carboxylic acid</span> Chemical compound

1-Pyrroline-5-carboxylic acid is a cyclic imino acid. Its conjugate base and anion is 1-pyrroline-5-carboxylate (P5C). In solution, P5C is in spontaneous equilibrium with glutamate-5-semialdhyde (GSA).

<span class="mw-page-title-main">Saccharopine dehydrogenase</span>

In molecular biology, the protein domain Saccharopine dehydrogenase (SDH), also named Saccharopine reductase, is an enzyme involved in the metabolism of the amino acid lysine, via an intermediate substance called saccharopine. The Saccharopine dehydrogenase enzyme can be classified under EC 1.5.1.7, EC 1.5.1.8, EC 1.5.1.9, and EC 1.5.1.10. It has an important function in lysine metabolism and catalyses a reaction in the alpha-Aminoadipic acid pathway. This pathway is unique to fungal organisms therefore, this molecule could be useful in the search for new antibiotics. This protein family also includes saccharopine dehydrogenase and homospermidine synthase. It is found in prokaryotes, eukaryotes and archaea.

<span class="mw-page-title-main">Aspartate-semialdehyde dehydrogenase</span> Amino-acid-synthesizing enzyme in fungi, plants and prokaryota

In enzymology, an aspartate-semialdehyde dehydrogenase is an enzyme that is very important in the biosynthesis of amino acids in prokaryotes, fungi, and some higher plants. It forms an early branch point in the metabolic pathway forming lysine, methionine, leucine and isoleucine from aspartate. This pathway also produces diaminopimelate which plays an essential role in bacterial cell wall formation. There is particular interest in ASADH as disabling this enzyme proves fatal to the organism giving rise to the possibility of a new class of antibiotics, fungicides, and herbicides aimed at inhibiting it.

In enzymology, a N-acetyl-gamma-glutamyl-phosphate reductase (EC 1.2.1.38) is an enzyme that catalyzes the chemical reaction

In enzymology, a saccharopine dehydrogenase (NAD+, L-glutamate-forming) (EC 1.5.1.9) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Saccharopine dehydrogenase (NADP+, L-glutamate-forming)</span>

In enzymology, a saccharopine dehydrogenase (NADP+, L-glutamate-forming) (EC 1.5.1.10) is an enzyme that catalyzes the chemical reaction

In enzymology, a saccharopine dehydrogenase (NADP+, L-lysine-forming) (EC 1.5.1.8) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">4-aminobutyrate transaminase</span> Class of enzymes

In enzymology, 4-aminobutyrate transaminase, also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">AASDHPPT</span> Protein-coding gene in the species Homo sapiens

L-aminoadipate-semialdehyde dehydrogenase-phosphopantetheinyl transferase is an enzyme that in humans is encoded by the AASDHPPT gene.

α-Aminoadipate pathway Chemical compound

The α-aminoadipate pathway is a biochemical pathway for the synthesis of the amino acid L-lysine. In the eukaryotes, this pathway is unique to the higher fungi and the euglenids. It has also been reported from bacteria of the genus Thermus.

<span class="mw-page-title-main">DHTKD1</span> Protein-coding gene in the species Homo sapiens

Dehydrogenase E1 and transketolase domain containing 1 is a protein that in humans is encoded by the DHTKD1 gene. This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q.

In enzymology, a D-2-hydroxyglutarate dehydrogenase is an enzyme that catalyzes the chemical reaction

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029695 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ↑ Zhu X, Tang G, Galili G (December 2002). "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. doi: 10.1074/jbc.M205466200 . PMID   12393892.
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  13. ↑ Meldrum BS (April 2000). "Glutamate as a neurotransmitter in the brain: review of physiology and pathology". The Journal of Nutrition. 130 (4S Suppl): 1007S–15S. doi: 10.1093/jn/130.4.1007s . PMID   10736372. Archived from the original on 2017-05-16. Retrieved 2017-03-05.
  14. ↑ "About Glutamate Toxicity". Huniting Disease Outreach for Education at Stanford (HOPES). Huntington’s Disease Society of America. 26 June 2011. Retrieved 2017-03-05.
  15. ↑ Ophardt CE (2003). "Acetyl CoA Crossroads Compound". Virtual ChemBook. Elmhurst College. Archived from the original on 2016-11-15. Retrieved 2017-03-05.
  16. 1 2 Markovitz PJ, Chuang DT, Cox RP (October 1984). "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. doi: 10.1016/S0021-9258(20)71252-4 . PMID   6434529.
  17. ↑ Jones EE, Broquist HP (June 1965). "Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis. Ii. studies in Saccharomyces cereviseae[sic]". The Journal of Biological Chemistry. 240 (6): 2531–6. doi: 10.1016/S0021-9258(18)97358-8 . PMID   14304864.
  18. ↑ Trupin JS, Broquist HP (June 1965). "Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis. I. studies in neurospora crassa". The Journal of Biological Chemistry. 240 (6): 2524–30. doi: 10.1016/S0021-9258(18)97357-6 . PMID   14304863.
  19. 1 2 Johansson E, Steffens JJ, Lindqvist Y, Schneider G (October 2000). "Crystal structure of saccharopine reductase from Magnaporthe grisea, an enzyme of the alpha-aminoadipate pathway of lysine biosynthesis". Structure. 8 (10): 1037–47. doi: 10.1016/s0969-2126(00)00512-8 . PMID   11080625.
  20. ↑ "AASS - aminoadipate-semialdehyde synthase". RCSB Protein Data Bank. Archived from the original on 2017-11-07. Retrieved 2017-03-06– via PDB.
  21. ↑ Hoffmann GF, Kolker S (2012). "Cerebral organic acid disorders and other disorders of lysine catabolism". In Saudubray JM, van den Berghe G, Walter JH (eds.). Inborn metabolic diseases diagnosis and treatment (5th ed.). Berlin: Springer. pp. 333–346. ISBN   978-3-642-15720-2.
  22. ↑ Saudubray JM, Rabier D (June 2007). "Biomarkers identified in inborn errors for lysine, arginine, and ornithine". The Journal of Nutrition. 137 (6 Suppl 2): 1669S–1672S. doi: 10.1093/jn/137.6.1669S . PMID   17513445.
  23. 1 2 vd Heiden C, Brink M, de Bree PK, v Sprang FJ, Wadman SK, de Pater JM, van Biervliet JP (1978). "Familial hyperlysinaemia due to L-lysine alpha-ketoglutarate reductase deficiency: results of attempted treatment". Journal of Inherited Metabolic Disease. 1 (3): 89–94. doi:10.1007/bf01805679. PMID   116084. S2CID   35326745.
  24. ↑ Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT (March 2006). "Mutations in antiquitin in individuals with pyridoxine-dependent seizures". Nature Medicine. 12 (3): 307–9. doi:10.1038/nm1366. PMID   16491085. S2CID   27940375.
  25. ↑ Goodman SI, Kratz LE, DiGiulio KA, Biery BJ, Goodman KE, Isaya G, Frerman FE (September 1995). "Cloning of glutaryl-CoA dehydrogenase cDNA, and expression of wild type and mutant enzymes in Escherichia coli". Human Molecular Genetics. 4 (9): 1493–8. doi:10.1093/hmg/4.9.1493. PMID   8541831.
  26. ↑ Dancis J, Hutzler J, Cox RP (May 1979). "Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on terminology". American Journal of Human Genetics. 31 (3): 290–9. PMC   1685795 . PMID   463877.
  27. ↑ Cederbaum SD, Shaw KN, Dancis J, Hutzler J, Blaskovics JC (August 1979). "Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria". The Journal of Pediatrics. 95 (2): 234–8. doi:10.1016/s0022-3476(79)80657-5. PMID   571908.
  28. ↑ 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 (September 2014). "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia". Human Molecular Genetics. 23 (18): 5009–16. doi: 10.1093/hmg/ddu218 . PMID   24847004.

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