Human angiotensin-converting enzyme in complex with BPPb
[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. 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). 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.
[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. [BNP_GLOBL] Blomhotin: inhibits the rabbit lung angiotensin-converting enzyme (ACE) with an IC(50) of 15 uM. Bradykinin-potentiating peptide A: causes no contraction of the rat gastric fundus smooth muscle even at high concentrations. Bradykinin-potentiating peptide B: inhibits the activity of the angiotensin-converting enzyme (ACE) by a preferential interaction with its C-domain. Also potentiates the hypotensive effects of bradykinin. Inhibits the rabbit lung ACE with an IC(50) of 1.1 uM. Bradykinin-potentiating peptide C: inhibits the activity of the angiotensin-converting enzyme (ACE) by interacting with the same potency to its C- and N-domains (PubMed:11994001). Inhibits the rabbit lung angiotensin-converting enzyme (ACE) with an IC(50) of 7.1 uM. Leu3-blomhotin: inhibits the rabbit lung angiotensin-converting enzyme (ACE) with an IC(50) of 46 uM. Synthetic Leu3-blomhotin contracts the rat gastric fundus smooth muscle in a rapid and transient manner. Bradykinin-potentiating peptide Ahb1: potentiates the bradykinin in vivo. Bradykinin-potentiating peptide Ahb2: does not show any bradykinin-potentiating effects. C-type natriuretic peptide: exhibits hypotensive and vasodepressor activity. Acts by activating natriuretic receptors (NPR1 and/or NPR2 and/or NPR3) (By similarity).
Publication Abstract from PubMed
Angiotensin-I converting enzyme (ACE), a two-domain dipeptidylcarboxypeptidase, is a key regulator of blood pressure as a result of its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Hence it is an important drug target in the treatment of cardiovascular diseases. ACE is primarily known for its ability to cleave angiotensin I (Ang I) to the vasoactive octapeptide angiotensin II (Ang II), but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a physiological modulator of hematopoiesis. For the first time we provide a detailed biochemical and structural basis for the domain selectivity of the natural peptide inhibitors of ACE, bradykinin potentiating peptide b and Ang II. Moreover, Ang II showed selective competitive inhibition of the carboxy-terminal domain of human somatic ACE providing evidence for a regulatory role in the human renin-angiotensin system (RAS).
Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides.,Masuyer G, Schwager SL, Sturrock ED, Isaac RE, Acharya KR Sci Rep. 2012;2:717. doi: 10.1038/srep00717. Epub 2012 Oct 9. PMID:23056909
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.