543:) 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 ornithine, while fumarate can enter the citric acid cycle.
523:
568:
non-functioning enzyme results in patients' accumulation of ammonia, argininosuccinate, and citrulline in the blood, and argininosuccinate is excreted in the urine. 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, in patients experiencing the disorder later in childhood.
559:
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 both a lens crystallin and an enzyme in other non-ocular tissues. Comparative studies of the δ-crystallins have been beneficial for understanding the enzymatic mechanism of the ASL reaction.
555:, 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-crystallins are the major structural eye lens water-soluble proteins of most birds, reptiles, and some other vertebrates.
240:
29:
531:
or
Threonine 161 of ASL is responsible for the proton abstraction of the Cβ, either directly or indirectly through a water molecule. 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.
506:. In humans, ASL is a multimer (tetramer) protein. An ASL disorder in humans can arise from mutations in the ASL gene, particularly mutations that affect the active site of the mutant multimer protein. ASL disorder is associated with considerable clinical and genetic heterogeneity which is considered to reflect the extensive intragenic complementation occurring among individual patients.
482:
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.
515:
571:
ASL is a key enzyme in the conversion of ammonia to urea through the urea cycle. Ammonia builds to toxic levels, resulting in hyperammonemia. 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
558:
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 δ-crystallin, 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
530:
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
575:
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
481:
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,
567:
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
477:
ASL is composed of four identical monomers; each monomer consisting of a single polypeptide chain between 49 and 52 kDa, 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
501:
of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. When a mixed multimer displays increased functionality relative to the unmixed multimers, the phenomenon is referred to as
870:"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"
1254:
934:
Chakraborty AR, Davidson A, Howell PL (February 1999). "Mutational analysis of amino acid residues involved in argininosuccinate lyase activity in duck delta II crystallin".
664:
Sampaleanu LM, Vallée F, Thompson GD, Howell PL (December 2001). "Three-dimensional structure of the argininosuccinate lyase frequently complementing allele Q286R".
194:
263:
213:
1118:
828:
Yu B, Thompson GD, Yip P, Howell PL, Davidson AR (December 2001). "Mechanisms for intragenic complementation at the human argininosuccinate lyase locus".
1247:
572:
limit the rate of synthesis of neurotransmitters such as glutamate, which can explain the developmental delay in argininosuccinic aciduria patients.
918:
1346:
478:
tetramer to form four active sites. Therefore, each ASL homotetramer has four active sites to catalyze the breakdown of argininosuccinate.
1240:
1291:
287:
447:
species. Mutations resulting in low activity of the enzyme increase levels of urea in the body and result in various side effects.
1162:
1111:
275:
206:
494:
often can form an aggregate referred to as a multimer. When a multimer is formed from polypeptides produced by two different
604:"Structural studies of duck delta2 crystallin mutants provide insight into the role of Thr161 and the 280s loop in catalysis"
268:
133:
157:
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1167:
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280:
218:
126:
1153:
715:
451:
345:
61:
1361:
974:"Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening"
56:
154:
1296:
1131:
1056:
807:
602:
Sampaleanu LM, Codding PW, Lobsanov YD, Tsai M, Smith GD, Horvatin C, Howell PL (December 2004).
78:
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and involved in the biosynthesis of arginine in all species and the production of urea in
369:
333:
114:
794:
769:
719:
90:
998:
973:
628:
603:
349:
189:
49:
770:"Intragenic complementation and the structure and function of argininosuccinate lyase"
239:
169:
1340:
738:
703:
164:
1060:
811:
28:
1232:
704:"Human argininosuccinate lyase: a structural basis for intragenic complementation"
458:(junction of the long and short arm) and the long (q) arm at position 11.2, from
304:
989:
379:
173:
1081:
909:
Pratt, Charlotte
Amerley; Voet, Donald; Voet, Judith G. (2008). "Figure 20.8".
33:
Crystal structure of duck argininosuccinate lyase with bound argininosuccinate.
1135:
1127:
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440:
311:
728:
459:
444:
1007:
955:
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886:
869:
849:
803:
685:
637:
747:
514:
1196:
316:
244:
Crystallographic structure of the human ASL monomer with labeled domains.
1177:
1052:
785:
619:
121:
102:
1039:
Jack, JJB (1982). "Actions of ammonia on the central nervous system".
947:
841:
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1021:
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109:
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1100:
1077:
GeneReviews/NCBI/NIH/UW entry on Urea Cycle
Disorders Overview
702:
Turner MA, Simpson A, McInnes RR, Howell PL (August 1997).
911:
Fundamentals of biochemistry: life at the molecular level
563:
Mutations and ASL deficiencies: argininosuccinic aciduria
439:
Located in liver cytosol, it is the fourth enzyme of the
1028:. U.S. Department of Health & Human Services. 2007.
526:
Argininosuccinate (in yellow) in the Active Site of ASL
413:-arginino)succinate arginine-lyase (fumarate-forming)
1310:
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43:
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1087:OMIM entries on Argininosuccinate Lyase Deficiency
972:Ficicioglu C, Mandell R, Shih VE (November 2009).
967:
965:
863:
861:
859:
649:
647:
868:Sampaleanu LM, Yu B, Howell PL (February 2002).
823:
821:
763:
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759:
757:
490:Multiple copies of a polypeptide encoded by a
1248:
1112:
697:
695:
8:
1255:
1241:
1233:
1149:
1119:
1105:
1097:
357:
238:
180:
27:
997:
885:
793:
737:
727:
627:
415:) catalyzes the reversible breakdown of
584:
16:Mammalian protein found in Homo sapiens
1041:Journal of Inherited Metabolic Disease
229:
18:
7:
462:64,984,963 to base pair 65,002,090.
1292:Formiminotransferase cyclodeaminase
1022:"ASL gene argininosuccinate lyase"
14:
431:-arginino)succinate = fumarate +
1163:Carbamoyl phosphate synthetase I
768:Yu B, Howell PL (October 2000).
1:
1187:Argininosuccinate synthetase
708:Proc. Natl. Acad. Sci. U.S.A
1347:Genes on human chromosome 7
1302:Phenylalanine ammonia-lyase
990:10.1016/j.ymgme.2009.06.011
450:The ASL gene is located on
1378:
1217:N-Acetylglutamate synthase
1168:Ornithine transcarbamylase
504:intragenic complementation
486:Intragenic complementation
467:intragenic complementation
576:necessary for catalysis.
356:
237:
179:
26:
1321:Argininosuccinate lyase
1287:Histidine ammonia-lyase
1192:Argininosuccinate lyase
729:10.1073/pnas.94.17.9063
393:argininosuccinate lyase
233:Argininosuccinate lyase
22:Argininosuccinate lyase
1326:Adenylosuccinate lyase
887:10.1074/jbc.M107465200
535:Role in the urea cycle
527:
519:
518:Proposed ASL mechanism
1222:Ornithine translocase
1132:amino acid metabolism
525:
517:
1210:Regulatory/transport
1154:mitochondrial matrix
913:. New York: Wiley.
774:Cell. Mol. Life Sci
720:1997PNAS...94.9063T
1297:Serine dehydratase
1053:10.1007/BF01805572
786:10.1007/PL00000646
620:10.1042/BJ20040656
528:
520:
465:ASL is related to
403:; systematic name
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1230:
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978:Mol. Genet. Metab
948:10.1021/bi982150g
920:978-0-470-12930-2
842:10.1021/bi011526e
678:10.1021/bi011525m
434:
430:
417:argininosuccinate
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401:argininosuccinase
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127:metabolic pathway
1369:
1314:: amidine-lyases
1280:: ammonia-lyases
1263:Carbon–nitrogen
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672:(51): 15570–80.
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614:(Pt 2): 437–47.
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1071:External links
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1352:Animal genes
1320:
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1044:
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1016:
984:(3): 273–7.
981:
977:
939:
936:Biochemistry
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830:Biochemistry
829:
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669:
666:Biochemistry
665:
611:
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547:δ-Crystallin
538:
529:
489:
480:
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454:between the
452:chromosome 7
449:
438:
424:
406:
404:
400:
396:
392:
390:
348:
91:BRENDA entry
1047:(S2): 104.
539:Ammonia (NH
391:The enzyme
370:Swiss-model
250:Identifiers
79:IntEnz view
39:Identifiers
1362:Urea cycle
1341:Categories
1146:Main cycle
1136:urea cycle
1128:Metabolism
608:Biochem. J
580:References
553:crystallin
456:centromere
441:urea cycle
366:Structures
361:Search for
323:Other data
148:structures
115:KEGG entry
62:9027-34-3
662:;
600:;
510:Mechanism
473:Structure
460:base pair
445:ureotelic
435:-arginine
329:EC number
305:NM_000048
264:NCBI gene
68:Databases
1197:Arginase
1092:GeneCard
1061:33915515
1008:19635676
956:10029537
896:11698398
850:11747433
804:11092456
795:11147086
686:11747432
638:15320872
380:InterPro
350:pter-q22
219:proteins
207:articles
195:articles
152:RCSB PDB
1178:cytosol
1139:enzymes
999:2773214
812:1254964
748:9256435
716:Bibcode
629:1134128
551:ASL, δ-
499:alleles
376:Domains
334:4.3.2.1
312:UniProt
174:QuickGO
139:profile
122:MetaCyc
57:CAS no.
50:4.3.2.1
1357:Lyases
1265:lyases
1059:
1006:
996:
954:
917:
894:
848:
810:
802:
792:
746:
736:
684:
636:
626:
496:mutant
346:Chr. 7
317:P04424
300:RefSeq
293:608310
255:Symbol
202:PubMed
184:Search
170:AmiGO
158:PDBsum
98:ExPASy
86:BRENDA
74:IntEnz
45:EC no.
1312:4.3.2
1278:4.3.1
1057:S2CID
808:S2CID
739:23030
341:Locus
134:PRIAM
1271:4.3)
1004:PMID
952:PMID
915:ISBN
892:PMID
846:PMID
800:PMID
744:PMID
682:PMID
659:1K62
634:PMID
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