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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/06/27 11:09:01」(JST)

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ASL (argininosuccinate lyase, also known as argininosuccinase) is an enzyme that catalyzes the reversible breakdown of argininosuccinate (ASA) producing the amino acid arginine and dicarboxylic acid fumarate. Located in liver cytosol, ASL is the fourth enzyme of the urea cycle and involved in the biosynthesis of arginine in all species and the production of urea in ureotelic species.^[2] Mutations in ASL, resulting low activity of the enzyme, increase levels of urea in the body and result in various side effects.

The ASL gene is located on chromosome 7 between the centromere (junction of the long and short arm) and the long (q) arm at position 11.2, from base pair 64,984,963 to base pair 65,002,090.

ASL is related to intragenic complementation.^[3]^[4]^[5]

Structure[edit]

ASL is composed of four identical monomers; each monomer consisting of a single polypeptide chain between 49 and 52 kDa,^[6] between 196 and 208 kDa for the entire tetrameric enzyme. Each monomer has three highly conserved regions remote from one another, but these regions cluster together in the tetramer to form four active sites. Therefore each ASL homotetramer has four active sites to catalyze the breakdown of argininosuccinate.

Each monomer in the ASL homotetramer is composed of three structural domains; all three are primarily alpha helical. Domains 1 and 3 are similar in structure as they both consist of helix-turn-helix motifs. Domain 1 of the monomer contains the amino terminus. Domain 2 contains one small beta sheet, nine alpha helices, and the carboxyl terminus. Three of the nine alpha helices on one monomer are engaged mainly in hydrophobic interactions with another monomer to form a dimer. Two dimers then associate by way of alpha helix, one from each monomer, to form a central 20-helix core. The association of all four monomers allows for the catalytic activity at each possible active site.^[4]

Mechanism[edit]

Proposed ASL mechanism

Argininosuccinate (in yellow) in the Active Site of ASL

The enzyme's cleavage of the argininosuccinate, to form fumarate and arginine, occurs through an E1cb elimination reaction. The base initiates the reaction by deprotonating the carbon adjacent to the arginine, or leaving group. Recent mutagenic studies of ASL homologues have shown that Histidine 162 or Threonine 161 of ASL is responsible for the proton abstraction of the Cβ, either directly or indirectly through a water molecule.^[6] Lysine 289 is thought to stabilize the negatively charged carbanion intermediate. Although there is no consensus of the catalytic acid that donates the proton to the imine functional group of the arginine product, some mutagenesis studies show serine 283 may be involved.^[6]

Role in the urea cycle[edit]

Ammonia (NH₃) is a toxic substance for many aerobic organisms and must be excreted. Some aquatic organisms release the toxin right directly into their environment, while other ureotelic species must convert their toxic nitrogen waste into non-toxic components, like uric acid or urea, through a series of catalyzed steps better known as the urea cycle. ASL catalyzes the fourth step in the cycle, following the action of argininosuccinate synthetase (ASS) in the liver cytosol. While ASS catalyzes the formation of argininosuccinate from citrulline and aspartate, ASL breaks the newly formed argininosuccinate into L-arginine and fumarate. L-arginine continues through the urea cycle to form urea and orinthine, while fumarate can enter the citric acid cycle.^[7]

δ-Crystallin[edit]

ASL, δ-crystallin, class II fumarase, aspartase, adenylosuccinase lyase, and 3-carboxy-cis,and cis-muconate lactonizing enzyme are all members of the same homotetrameric superfamily of enzymes, in which most catalyze the same type of elimination reactions where a C-O or C-N bond is broken and fumarate is released as a product. δ-crysatllins are the major structural eye lens water soluble proteins of most birds, reptiles, and some other vertebrates.^[4] Within the superfamily, ASL is most closely related to δ-Crystallin in amino acid sequence and in protein fold structure. There are two isoforms of the crystalline, δI and δII. These two isoforms conserve 69% and 71% of the ASL amino acid sequence, respectively, but only the δII isoform retains the same enzymatic activity as ASL. The similarities have led researches to believe that these crystallins have evolved from the recruitment to the lens of preexisting metabolic enzymes, like ASL, by a process called 'gene sharing'. The same gene product functions as a both a lens crystallin and an enzyme in other non-ocular tissues. Comparative studies of the δ-crystallins have been most beneficial for understanding the enzymatic mechanism of the ASL reaction.^[8]

Mutations and ASL deficiencies: argininosuccinic aciduria[edit]

Mutations in the human ASL gene causes argininosuccinic aciduria, a rare autosomal recessive disorder, and results in deficiencies of the urea cycle. Argininosuccinate lyase is an intermediate enzyme in the urea synthesis pathway and its function is imperative to the continuation of the cycle. A non-functioning enzyme results in patients' accumulation of ammonia, argininosuccinate, and citrulline in the blood, and argininosuccinate is excreted in the urine.^[9] Other resulting symptoms include lethargy, vomiting, hypothermia, hyperventilation, hepatomegaly and progressive encephalopathy in infant patients, and abnormal hair growth, hepatic fibrosis, episodic vomiting, growth and developmental delay,^[9] in patients experiencing the disorder later in childhood.

ASL is a key enzyme in the conversion of ammonia to urea through the urea cycle. Ammonia builds to toxic levels, resulting in hyperammonemia.^[10] Ammonia is toxic in part because it affects the nervous system. There is biochemical evidence that shows rises in ammonia can inhibit glutaminase and therefore limit the rate of synthesis of neurotransmitters such as glutamate,^[11] which can explain the developmental delay in argininosuccinic aciduria patients.

One mutation in patients with argininosuccinic aciduria occurs when glutamine 286 is mutated to arginine. The enzyme now has a positively charged arginine in place of a neutrally charged glutamine and studies suggest this change may sterically and/or electrostatically hinder a conformational change necessary for catalysis.

References[edit]

^ PDB 1TJW; Sampaleanu LM, Codding PW, Lobsanov YD, Tsai M, Smith GD, Horvatin C, Howell PL (December 2004). "Structural studies of duck delta2 crystallin mutants provide insight into the role of Thr161 and the 280s loop in catalysis". Biochem. J. 384 (Pt 2): 437–47. doi:10.1042/BJ20040656. PMC 1134128. PMID 15320872.
^ ^a ^b PDB 1K62; Sampaleanu LM, Vallée F, Thompson GD, Howell PL (December 2001). "Three-dimensional structure of the argininosuccinate lyase frequently complementing allele Q286R". Biochemistry 40 (51): 15570–80. doi:10.1021/bi011525m. PMID 11747432.
^ Turner MA, Simpson A, McInnes RR, Howell PL (August 1997). "Human argininosuccinate lyase: a structural basis for intragenic complementation". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9063–8. doi:10.1073/pnas.94.17.9063. PMC 23030. PMID 9256435.
^ ^a ^b ^c Yu B, Howell PL (October 2000). "Intragenic complementation and the structure and function of argininosuccinate lyase". Cell. Mol. Life Sci. 57 (11): 1637–51. doi:10.1007/PL00000646. PMID 11092456.
^ Yu B, Thompson GD, Yip P, Howell PL, Davidson AR (December 2001). "Mechanisms for intragenic complementation at the human argininosuccinate lyase locus". Biochemistry 40 (51): 15581–90. doi:10.1021/bi011526e. PMID 11747433.
^ ^a ^b ^c Sampaleanu LM, Yu B, Howell PL (February 2002). "Mutational analysis of duck delta 2 crystallin and the structure of an inactive mutant with bound substrate provide insight into the enzymatic mechanism of argininosuccinate lyase". J. Biol. Chem. 277 (6): 4166–75. doi:10.1074/jbc.M107465200. PMID 11698398.
^ Pratt, Charlotte Amerley; Voet, Donald; Voet, Judith G. (2008). "Figure 20.8". Fundamentals of biochemistry: life at the molecular level. New York: Wiley. ISBN 0-470-12930-1.
^ Chakraborty AR, Davidson A, Howell PL (February 1999). "Mutational analysis of amino acid residues involved in argininosuccinate lyase activity in duck delta II crystallin". Biochemistry 38 (8): 2435–43. doi:10.1021/bi982150g. PMID 10029537.
^ ^a ^b Ficicioglu C, Mandell R, Shih VE (November 2009). "Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening". Mol. Genet. Metab. 98 (3): 273–7. doi:10.1016/j.ymgme.2009.06.011. PMC 2773214. PMID 19635676.
^ National Library of Medicine (2007). Genetics Home Reference.
^ Jack, JJB (1982). "Actions of ammonia on the central nervous system". Journal of Inherited Metabolic Disease 5 (S2): 104. doi:10.1007/BF01805572.

External links[edit]

GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview
GeneReviews/NCBI/NIH/UW entry on Argininosuccinate Lyase Deficiency
OMIM entries on Argininosuccinate Lyase Deficiency
GeneCard

UpToDate Contents

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1. 尿素サイクル障害：臨床的特徴および診断 urea cycle disorders clinical features and diagnosis
2. 尿素サイクル障害：管理 urea cycle disorders management
3. クレアチン代謝の先天性疾患 congenital disorders of creatine metabolism
4. 幼児および小児における精密な神経学的評価 detailed neurologic assessment of infants and children
5. 脱毛の評価および診断 evaluation and diagnosis of hair loss

English Journal

Mutations and Polymorphisms in the Human Argininosuccinate Lyase (ASL) Gene.

Balmer C, Pandey AV, Rüfenacht V, Nuoffer JM, Fang P, Wong LJ, Häberle J.Author information Division of Metabolism, University Children's Hospital, Zurich, Switzerland; Children's Research Center, Zurich, Switzerland.AbstractArgininosuccinate lyase deficiency (ASLD) is caused by a defect of the urea cycle enzyme argininosuccinate lyase (ASL) encoded by the ASL gene. Patients often present early after birth with hyperammonemia but can also manifest outside the neonatal period mainly triggered by excessive protein catabolism. Clinical courses comprise asymptomatic individuals who only excrete the biochemical marker, argininosuccinic acid, in urine, and patients who succumb to their first hyperammonemic decompensation. Some patients without any hyperammonemia develop severe neurological disease. Here, we are providing an update on the molecular basis of ASLD by collecting all published (n = 67) as well as novel mutations (n = 67) of the ASL gene. We compile data on all 160 different genotypes ever identified in 223 ASLD patients, including clinical courses whenever available. Finally, we are presenting structural considerations focusing on the relevance of mutations for ASL homotetramer formation. ASLD can be considered as a panethnic disease with only single founder mutations identified in the Finnish (c.299T>C, p.Ile100Thr) and Arab (c.1060C>T, p.Gln354*) population. Most mutations are private with only few genotypes recurring in unrelated patients. The majority of mutations are missense changes including some with more frequent occurrence such as p.Arg12Gln, p.Ile100Thr, p.Val178Met, p.Arg186Trp, p.Glu189Gly, p.Gln286Arg, and p.Arg385Cys.
Human mutation.Hum Mutat.2014 Jan;35(1):27-35. doi: 10.1002/humu.22469. Epub 2013 Nov 25.
Argininosuccinate lyase deficiency (ASLD) is caused by a defect of the urea cycle enzyme argininosuccinate lyase (ASL) encoded by the ASL gene. Patients often present early after birth with hyperammonemia but can also manifest outside the neonatal period mainly triggered by excessive protein catabol
PMID 24166829

Two different approaches to restore renal nitric oxide and prevent hypertension in young spontaneously hypertensive rats: l-citrulline and nitrate.

Chien SJ1, Lin KM1, Kuo HC1, Huang CF1, Lin YJ1, Huang LT2, Tain YL3.Author information 1Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.2Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan; Department of Traditional Chinese Medicine, Chang Gung University, Linkow, Taiwan.3Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan. Electronic address: tainyl@hotmail.com.AbstractNitric oxide (NO) deficiency mediates oxidative stress in the kidney and is involved in the development of hypertension. NO synthesis occurs via 2 pathways: nitric oxide synthase (NOS) dependent and NOS-independent. We tested whether the development of hypertension is prevented by restoration of NO by dietary l-citrulline or nitrate supplementation in young spontaneously hypertensive rats (SHRs). Male SHRs and normotensive Wistar Kyoto control rats (WKYs)s age 4 weeks were assigned to 4 groups: untreated SHRs and WKYs, and SHRs and WKYs that received 0.25% l-citrulline for 8 weeks. In our second series of studies, we replaced l-citrulline with 1 mmol/kg/d sodium nitrate. All rats were sacrificed at age 12 weeks. We found an increase in the blood pressure of SHRs was prevented by dietary supplementation of l-citrulline or nitrate. Both treatments restored NO bioavailability and reduced oxidative stress in SHR kidneys. l-Citrulline therapy reduced levels of l-arginine and asymmetric dimethylarginine (ADMA)-an endogenous inhibitor of NOS-and increased the l-arginine-to-ADMA ratio in SHR kidneys. Nitrate treatment reduced plasma levels of l-arginine and ADMA concurrently in SHRs. Our findings suggest that both NOS-dependent and -independent approaches in the prehypertensive stage toward augmentation of NO can prevent the development of hypertension in young SHRs.
Translational research : the journal of laboratory and clinical medicine.Transl Res.2014 Jan;163(1):43-52. doi: 10.1016/j.trsl.2013.09.008. Epub 2013 Oct 8.
Nitric oxide (NO) deficiency mediates oxidative stress in the kidney and is involved in the development of hypertension. NO synthesis occurs via 2 pathways: nitric oxide synthase (NOS) dependent and NOS-independent. We tested whether the development of hypertension is prevented by restoration of NO
PMID 24113064

Cloning, expression, purification, crystallization and preliminary X-ray studies of argininosuccinate lyase (Rv1659) from Mycobacterium tuberculosis.

Paul A, Mishra A, Surolia A, Vijayan M.Author information Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India.AbstractThe last enzyme in the arginine-biosynthesis pathway, argininosuccinate lyase, from Mycobacterium tuberculosis has been cloned, expressed, purified and crystallized, and preliminary X-ray studies have been carried out on the crystals. The His-tagged tetrameric enzyme with a subunit molecular weight of 50.9 kDa crystallized with two tetramers in the asymmetric unit of the orthorhombic unit cell, space group P212121. Molecular-replacement calculations and self-rotation calculations confirmed the space group and the tetrameric nature of the molecule.
Acta crystallographica. Section F, Structural biology and crystallization communications.Acta Crystallogr Sect F Struct Biol Cryst Commun.2013 Dec;69(Pt 12):1422-4. doi: 10.1107/S1744309113031138. Epub 2013 Nov 29.
The last enzyme in the arginine-biosynthesis pathway, argininosuccinate lyase, from Mycobacterium tuberculosis has been cloned, expressed, purified and crystallized, and preliminary X-ray studies have been carried out on the crystals. The His-tagged tetrameric enzyme with a subunit molecular weight
PMID 24316845

Japanese Journal

短腸ラットモデルにおけるシトルリン補充療法の有用性および citrulline‐nitric oxide cycle の分子生物学的検討

外科と代謝・栄養 48(1), 9-20, 2014
NAID 130004638724

A quantitative study on arginine synthesis from argininosuccinic acid and citrulline by crude enzymes of cattle kidney

Animal science journal 74(4), 289-294, 2003-08-01
NAID 10018627796

A Novel Stop Codon Mutation (X465Y) in the Argininosuccinate Lyase Gene in a Patient with Argininosuccinic Aciduria

THE TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 198(2), 119-124, 2002-10-01
NAID 50000726766

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リンク元	「AL」「アルギニノコハク酸リアーゼ」「AL deficiency」
拡張検索	「argininosuccinate lyase deficiency」
関連記事	「argininosuccinate」

「AL」

Argininosuccinate lyase
	; Crystallographic structure of the human ASL monomer with labeled domains.
Identifiers
Symbol	ASL
Entrez	435
HUGO	746
OMIM	608310
RefSeq	NM_000048
UniProt	P04424
Other data
EC number	4.3.2.1
Locus	Chr. 7 pter-q22

Search
PMC	articles
PubMed	articles
NCBI	proteins

Argininosuccinate lyase
	; Crystal structure of duck argininosuccinate lyase with bound argininosuccinate.
Identifiers
EC number	4.3.2.1
CAS number	9027-34-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins

　　[★]

「アルギニノコハク酸リアーゼ」

　　[★]

英: argininosuccinate lyase, AL
同: アルギニノスクシナーゼ argininosuccinase
関: [[]]

「AL deficiency」

　　[★]

同: argininosuccinate lyase

「argininosuccinate lyase deficiency」

　　[★] アルギニノコハク酸尿症。アルギニノコハク酸リアーゼ欠損症

「argininosuccinate」

　　[★]

アルギニノコハク酸、アルギノコハク酸

関: argininosuccinic acid

argininosuccinic acid

[pmid15320872-1] PDB 1TJW; Sampaleanu LM, Codding PW, Lobsanov YD, Tsai M, Smith GD, Horvatin C, Howell PL (December 2004). "Structural studies of duck delta2 crystallin mutants provide insight into the role of Thr161 and the 280s loop in catalysis". Biochem. J. 384 (Pt 2): 437–47. doi:10.1042/BJ20040656. PMC 1134128. PMID 15320872.

[Sampaleanu_2001-2] PDB 1K62; Sampaleanu LM, Vallée F, Thompson GD, Howell PL (December 2001). "Three-dimensional structure of the argininosuccinate lyase frequently complementing allele Q286R". Biochemistry 40 (51): 15570–80. doi:10.1021/bi011525m. PMID 11747432.

[pmid9256435-3] Turner MA, Simpson A, McInnes RR, Howell PL (August 1997). "Human argininosuccinate lyase: a structural basis for intragenic complementation". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9063–8. doi:10.1073/pnas.94.17.9063. PMC 23030. PMID 9256435.

[pmid11092456-4] Yu B, Howell PL (October 2000). "Intragenic complementation and the structure and function of argininosuccinate lyase". Cell. Mol. Life Sci. 57 (11): 1637–51. doi:10.1007/PL00000646. PMID 11092456.

[pmid11747433-5] Yu B, Thompson GD, Yip P, Howell PL, Davidson AR (December 2001). "Mechanisms for intragenic complementation at the human argininosuccinate lyase locus". Biochemistry 40 (51): 15581–90. doi:10.1021/bi011526e. PMID 11747433.

[Sampaleanu_2002-6] Sampaleanu LM, Yu B, Howell PL (February 2002). "Mutational analysis of duck delta 2 crystallin and the structure of an inactive mutant with bound substrate provide insight into the enzymatic mechanism of argininosuccinate lyase". J. Biol. Chem. 277 (6): 4166–75. doi:10.1074/jbc.M107465200. PMID 11698398.

[isbn0-470-12930-1-7] Pratt, Charlotte Amerley; Voet, Donald; Voet, Judith G. (2008). "Figure 20.8". Fundamentals of biochemistry: life at the molecular level. New York: Wiley. ISBN 0-470-12930-1.

[Chakraborty-8] Chakraborty AR, Davidson A, Howell PL (February 1999). "Mutational analysis of amino acid residues involved in argininosuccinate lyase activity in duck delta II crystallin". Biochemistry 38 (8): 2435–43. doi:10.1021/bi982150g. PMID 10029537.

[Ficicioglu_2009-9] Ficicioglu C, Mandell R, Shih VE (November 2009). "Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening". Mol. Genet. Metab. 98 (3): 273–7. doi:10.1016/j.ymgme.2009.06.011. PMC 2773214. PMID 19635676.

[GeneticsHomeRef-10] National Library of Medicine (2007). Genetics Home Reference.

[11] Jack, JJB (1982). "Actions of ammonia on the central nervous system". Journal of Inherited Metabolic Disease 5 (S2): 104. doi:10.1007/BF01805572.

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argininosuccinate lyase