| Structural highlights
Disease
ARGI1_HUMAN Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:207800; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.[1] [2]
Function
ARGI1_HUMAN
Publication Abstract from PubMed
Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.
2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors.,Golebiowski A, Paul Beckett R, Van Zandt M, Ji MK, Whitehouse D, Ryder TR, Jagdmann E, Andreoli M, Mazur A, Padmanilayam M, Cousido-Siah A, Mitschler A, Ruiz FX, Podjarny A, Schroeter H Bioorg Med Chem Lett. 2013 Apr 1;23(7):2027-30. doi: 10.1016/j.bmcl.2013.02.024. , Epub 2013 Feb 13. PMID:23453840[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Uchino T, Haraguchi Y, Aparicio JM, Mizutani N, Higashikawa M, Naitoh H, Mori M, Matsuda I. Three novel mutations in the liver-type arginase gene in three unrelated Japanese patients with argininemia. Am J Hum Genet. 1992 Dec;51(6):1406-12. PMID:1463019
- ↑ Uchino T, Snyderman SE, Lambert M, Qureshi IA, Shapira SK, Sansaricq C, Smit LM, Jakobs C, Matsuda I. Molecular basis of phenotypic variation in patients with argininemia. Hum Genet. 1995 Sep;96(3):255-60. PMID:7649538
- ↑ Golebiowski A, Paul Beckett R, Van Zandt M, Ji MK, Whitehouse D, Ryder TR, Jagdmann E, Andreoli M, Mazur A, Padmanilayam M, Cousido-Siah A, Mitschler A, Ruiz FX, Podjarny A, Schroeter H. 2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors. Bioorg Med Chem Lett. 2013 Apr 1;23(7):2027-30. doi: 10.1016/j.bmcl.2013.02.024. , Epub 2013 Feb 13. PMID:23453840 doi:http://dx.doi.org/10.1016/j.bmcl.2013.02.024
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