Angiotensin Converting Enzyme 1

Function

Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity (PubMed:15615692, PubMed:20826823, PubMed:2558109, PubMed:4322742, PubMed:7523412, PubMed:7683654). Composed of two similar catalytic domains, each possessing a functional active site, with different selectivity for substrates (PubMed:10913258, PubMed:1320019, PubMed:1851160, PubMed:19773553, PubMed:7683654, PubMed:7876104). Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin (PubMed:11432860, PubMed:1851160, PubMed:19773553, PubMed:23056909, PubMed:4322742). Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response (PubMed:15615692, PubMed:2558109, PubMed:4322742, PubMed:6055465, PubMed:6270633, PubMed:7683654). Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins (PubMed:15615692, PubMed:6208535, PubMed:6270633, PubMed:656131). Catalyzes degradation of different enkephalin neuropeptides (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe and possibly Met-enkephalin-Arg-Gly-Leu) (PubMed:2982830, PubMed:6270633, PubMed:656131). Acts as a regulator of synaptic plasticity in the nucleus accumbens of the brain by mediating cleavage of Met-enkephalin-Arg-Phe, a strong ligand of Mu-type opioid receptor OPRM1, into Met-enkephalin (By similarity). Met-enkephalin-Arg-Phe cleavage by ACE decreases activation of OPRM1, leading to long-term synaptic potentiation of glutamate release (By similarity). Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) (PubMed:26403559, PubMed:7876104, PubMed:8257427, PubMed:8609242). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:18077343). Involved in amyloid-beta metabolism by catalyzing degradation of Amyloid-beta protein 40 and Amyloid-beta protein 42 peptides, thereby preventing plaque formation (PubMed:11604391, PubMed:16154999, PubMed:19773553). Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones (PubMed:10336644, PubMed:2983326, PubMed:7683654, PubMed:9371719). Degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) and amyloid-beta proteins is mediated by the N-terminal catalytic domain, while angiotensin I and cholecystokinin cleavage is mediated by the C-terminal catalytic region (PubMed:10336644, PubMed:19773553, PubMed:7876104).

Angiotensin-converting enzyme, soluble form

Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region.

Isoform Testis-specific

Isoform produced by alternative promoter usage that is specifically expressed in spermatocytes and adult testis, and which is required for male fertility (PubMed:1651327, PubMed:1668266). In contrast to somatic isoforms, only contains one catalytic domain (PubMed:1651327, PubMed:1668266). Acts as a dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of substrates (PubMed:1668266, PubMed:24297181). The identity of substrates that are needed for male fertility is unknown (By similarity). May also have a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. The GPIase activity was reported to be essential for the egg-binding ability of the sperm (By similarity). This activity is however unclear and has been challenged by other groups, suggesting that it may be indirect (By similarity).

Involvement in disease

Ischemic stroke

ISCHSTR

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.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Renal tubular dysgenesis

RTD

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).

None

The disease is caused by variants affecting the gene represented in this entry.

Microvascular complications of diabetes 3

MVCD3

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.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Intracerebral hemorrhage

ICH

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.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Post-translational modifications

Angiotensin-converting enzyme, soluble form

Produced following proteolytic cleavage by secretase enzymes that cleave the transmembrane form in the juxtamembrane stalk region upstream of the transmembrane region (PubMed:10769174, PubMed:11274151, PubMed:7499427, PubMed:8253769). Cleavage can take place at different sites of the juxtamembrane stalk region (PubMed:10769174, PubMed:11274151, PubMed:7499427, PubMed:8253769).

Phosphorylated by CK2 on Ser-1299; which allows membrane retention (PubMed:12386153). Phosphorylated on tyrosine residues on its extracellular part, promoting cleavage by secretase enzymes and formation of the soluble form (Angiotensin-converting enzyme, soluble form) (By similarity).

Sequence similarities

Belongs to the peptidase M2 family.

Tissue specificity

Ubiquitously expressed, with highest levels in lung, kidney, heart, gastrointestinal system and prostate.

Isoform Testis-specific

Specifically expressed in spermatocytes and adult testis.

Cellular localization

• Cell membrane
• Single-pass type I membrane protein
• Cytoplasm
• Detected in both cell membrane and cytoplasm in neurons.
• Angiotensin-converting enzyme, soluble form
• Secreted
• Isoform Testis-specific
• Cell membrane
• Single-pass type I membrane protein
• Secreted
• The testis-specific isoform can be cleaved before the transmembrane region, releasing a soluble form.

Alternative names

• DCP
• DCP1
• DCP1
• DCP
• ACE
• Angiotensin-converting enzyme
• ACE
• Dipeptidyl carboxypeptidase I
• Kininase II

Database links

• entrezGene:1636
• omim:106180
• swissprot:P12821

Target type

Proteins

Primary research area

Cardiovascular

Other research areas

• Neuroscience

Molecular weight

149715Da