| Structural highlights
4ca6 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: | 4ca5, 4ca7, 4ca8 |
| Activity: | Peptidyl-dipeptidase A, with EC number 3.4.15.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[ACE_HUMAN] Genetic variations in ACE may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.[1] Defects in ACE are a cause of renal tubular dysgenesis (RTD) [MIM:267430]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).[2] Genetic variations in ACE are associated with susceptibility to microvascular complications of diabetes type 3 (MVCD3) [MIM:612624]. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Defects in ACE are a cause of susceptibility to intracerebral hemorrhage (ICH) [MIM:614519]. A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke.[3]
Function
[ACE_HUMAN] Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety.
Publication Abstract from PubMed
Human somatic angiotensin-I converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase and a central component of the renin angiotensin-aldosterone system (RAAS). Its involvement in the modulation of physiological actions of peptide hormones has positioned ACE as an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the crystal structures of the two catalytic domains of human ACE (N- and C-) in complex with FI, the S enantiomer of the phosphinic ACE/ECE-1 (endothelin converting enzyme) dual inhibitor FII, to a resolution of 1.91A and 1.85 A, respectively. In addition, we have determined the structure of AnCE (an ACE homologue from Drosophila melanogaster) in complex with both isomers. The inhibitor FI (S configuration) can adapt to the active site of ACE catalytic domains and shows key differences in its binding mechanism mostly through the reorientation of the isoxazole phenyl side group at the P1 ' position, compared to FII (R configuration). Differences in binding are also observed between FI and FII in complex with AnCE. Thus, the new structures of the ACE-inhibitor complexes presented here provide useful information for further exploration of ACE inhibitor pharmacophores involving phosphinic peptides and illustrate the role of chirality in enhancing drug specificity. This article is protected by copyright. All rights reserved.
Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin-I converting enzyme.,Masuyer G, Akif M, Czarny B, Beau F, Schwager SL, Sturrock ED, Isaac RE, Dive V, Acharya KR FEBS J. 2013 Nov 29. doi: 10.1111/febs.12660. PMID:24289879[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004 Nov;61(11):1652-61. PMID:15534175 doi:61/11/1652
- ↑ Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623
- ↑ Slowik A, Turaj W, Dziedzic T, Haefele A, Pera J, Malecki MT, Glodzik-Sobanska L, Szermer P, Figlewicz DA, Szczudlik A. DD genotype of ACE gene is a risk factor for intracerebral hemorrhage. Neurology. 2004 Jul 27;63(2):359-61. PMID:15277638
- ↑ Masuyer G, Akif M, Czarny B, Beau F, Schwager SL, Sturrock ED, Isaac RE, Dive V, Acharya KR. Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin-I converting enzyme. FEBS J. 2013 Nov 29. doi: 10.1111/febs.12660. PMID:24289879 doi:http://dx.doi.org/10.1111/febs.12660
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