| Structural highlights
4hww is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 1d3v, 2aeb, 4hxq, 4hze |
| Gene: | ARG1 (HUMAN) |
| Activity: | Arginase, with EC number 3.5.3.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Publication Abstract from PubMed
Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent alpha,alpha-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.
Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury.,Van Zandt MC, Whitehouse DL, Golebiowski A, Ji MK, Zhang M, Beckett RP, Jagdmann GE, Ryder TR, Sheeler R, Andreoli M, Conway B, Mahboubi K, D'Angelo G, Mitschler A, Cousido-Siah A, Ruiz FX, Howard EI, Podjarny AD, Schroeter H J Med Chem. 2013 Mar 28;56(6):2568-80. doi: 10.1021/jm400014c. Epub 2013 Mar 8. PMID:23472952[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Van Zandt MC, Whitehouse DL, Golebiowski A, Ji MK, Zhang M, Beckett RP, Jagdmann GE, Ryder TR, Sheeler R, Andreoli M, Conway B, Mahboubi K, D'Angelo G, Mitschler A, Cousido-Siah A, Ruiz FX, Howard EI, Podjarny AD, Schroeter H. Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury. J Med Chem. 2013 Mar 28;56(6):2568-80. doi: 10.1021/jm400014c. Epub 2013 Mar 8. PMID:23472952 doi:http://dx.doi.org/10.1021/jm400014c
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