Pathways

Metabolites of Acalabrutinib are predicted with biotransformer.

Angiotensin-converting enzyme (EC 3.4.15.1), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors are widely used as pharmaceutical drugs for treatment of cardiovascular diseases. Other lesser known functions of ACE are degradation of bradykinin, substance P, and amyloid beta-protein. Angiotensin converting enzyme (ACE) is well known for its dual actions in converting inactive Ang I to active Ang II and degrade active bradykinin (BK), which play an important role in the control of blood pressure. Since the bottle neck step is the production of pressor Ang II, this was targeted pharmacologically in 1970s and successful ACE inhibitors such as captopril were produced to treat hypertension. ACE2 was identified as the receptor for SARS (severe acute respiratory syndrome) coronavirus, which caused the outbreak of an epidemic in 2002–2003. Two isozymes of ACE are present in mammals: somatic ACE and testis ACE. Somatic ACE possesses two catalytic domains (N- and C-domains) and a C-terminal transmembrane segment (stalk). Somatic and testis ACEs in humans contain 1,306 and 665 aa residues, respectively. Testis ACE only possesses one catalytic domain. Both catalytic domains are zinc-metallopeptidase with the active motif HEMGH where the two histidine residues coordinate the zinc ion. The stalk anchors the enzyme on the membrane and is susceptible to be cleaved by shedding enzymes, resulting in plasma ACE activity. Somatic ACE is expressed in various tissues including blood vessels, kidney, intestine, adrenal gland, liver, and uterus, and is especially abundant in highly vascular organs such as retina and lung. Testis ACE is expressed by postmeiotic male germ cells and high-level expression is found in round and elongated spermatids. ACE2 is expressed in lung, liver, intestine, brain, testis, heart, and kidney. Lung possesses the highest amount of ACE. Expression of ACE is affected by steroids and thyroid hormone, but the details of the regulation are not clear. ACE is under promoter regulation by hypoxia-inducing factor 1α (HIF-1α), which upregulates the ACE expression under hypoxic conditions, resulting in an increase in Ang II concentration. The well-known function of ACE is the conversion of Ang I to Ang II and degradation of BK, which all play an important role in controlling blood pressure. ACE also acts on other natural substrates including encephalin, neurotensin, and substance P. Besides being involved in blood pressure control, ACE possesses widespread functions including renal development, male fertility, hematopoiesis, erythropoiesis, myelopoiesis, and immune responses. ACE has been the target of hypertension control since the 1970s. ACE inhibitors are prescribed as the sole or combinational treatment of high blood pressure, for the dual effects of lowering Ang II and slowing down BK degradation. Angiotensin II binds to the type 1 angiotensin II receptor (AT1), which sets off a number of actions that result in vasoconstriction and therefore increased blood pressure. The B2 (bradykinin 2) receptor is constitutively expressed and participates in bradykinin's vasodilatory role, it is a G protein coupled receptor.