Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDF1964)

• DOT Name: Angiotensin-converting enzyme (ACE)
• Synonyms: ACE; EC 3.4.15.1; Dipeptidyl carboxypeptidase I; Kininase II; CD antigen CD143
• Gene Name: ACE
• Related Disease:
  Acute kidney injury
  Adenocarcinoma
  Alcohol dependence
  Arrhythmia
  Autism
  Brain ischaemia
  Gastric cancer
  Gaucher disease type I
  Gaucher disease type II
  Gaucher disease type III
  Glomerulonephritis
  Glomerulosclerosis
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Hypotension
  Lung neoplasm
  Non-alcoholic steatohepatitis
  Osteoporosis
  Pre-eclampsia
  Primary biliary cholangitis
  Prostate neoplasm
  Pulmonary fibrosis
  Pulmonary hypertension
  Renal fibrosis
  Renal tubular dysgenesis
  Renal tubular dysgenesis of genetic origin
  Ventricular fibrillation
  Viral pneumonia
  Bipolar depression
  Familial atrial fibrillation
  Gaucher disease
  Glycogen storage disease V
  Staphylococcus aureus infection
  Staphylococcus infection
  Coeliac disease
  Familial Alzheimer disease
  Fetal growth restriction
  Gastric neoplasm
  Intracerebral hemorrhage
  Meningococcal disease
  Non-alcoholic fatty liver disease
• UniProt ID: ACE_HUMAN
• PDB ID: 1O86 ; 1O8A ; 1UZE ; 1UZF ; 2C6F ; 2C6N ; 2IUL ; 2IUX ; 2OC2 ; 2XY9 ; 2XYD ; 2YDM ; 3BKK ; 3BKL ; 3L3N ; 3NXQ ; 4APH ; 4APJ ; 4BXK ; 4BZR ; 4BZS ; 4C2N ; 4C2O ; 4C2P ; 4C2Q ; 4C2R ; 4CA5 ; 4CA6 ; 4UFA ; 4UFB ; 5AM8 ; 5AM9 ; 5AMA ; 5AMB ; 5AMC ; 6EN5 ; 6EN6 ; 6F9R ; 6F9T ; 6F9U ; 6F9V ; 6H5W ; 6H5X ; 6QS1 ; 6TT1 ; 6TT3 ; 6TT4 ; 6ZPQ ; 6ZPT ; 6ZPU ; 7Q24 ; 7Q25 ; 7Q26 ; 7Q27 ; 7Q28 ; 7Q29 ; 7Q3Y ; 7Q49 ; 7Q4C ; 7Q4D ; 7Q4E ; 7Z6Z ; 7Z70 ; 8QFX ; 8QHL
• EC Number: 3.4.15.1
• Pfam ID: PF01401
• Sequence:
  MGAASGRRGPGLLLPLPLLLLLPPQPALALDPGLQPGNFSADEAGAQLFAQSYNSSAEQV
  LFQSVAASWAHDTNITAENARRQEEAALLSQEFAEAWGQKAKELYEPIWQNFTDPQLRRI
  IGAVRTLGSANLPLAKRQQYNALLSNMSRIYSTAKVCLPNKTATCWSLDPDLTNILASSR
  SYAMLLFAWEGWHNAAGIPLKPLYEDFTALSNEAYKQDGFTDTGAYWRSWYNSPTFEDDL
  EHLYQQLEPLYLNLHAFVRRALHRRYGDRYINLRGPIPAHLLGDMWAQSWENIYDMVVPF
  PDKPNLDVTSTMLQQGWNATHMFRVAEEFFTSLELSPMPPEFWEGSMLEKPADGREVVCH
  ASAWDFYNRKDFRIKQCTRVTMDQLSTVHHEMGHIQYYLQYKDLPVSLRRGANPGFHEAI
  GDVLALSVSTPEHLHKIGLLDRVTNDTESDINYLLKMALEKIAFLPFGYLVDQWRWGVFS
  GRTPPSRYNFDWWYLRTKYQGICPPVTRNETHFDAGAKFHVPNVTPYIRYFVSFVLQFQF
  HEALCKEAGYEGPLHQCDIYRSTKAGAKLRKVLQAGSSRPWQEVLKDMVGLDALDAQPLL
  KYFQPVTQWLQEQNQQNGEVLGWPEYQWHPPLPDNYPEGIDLVTDEAEASKFVEEYDRTS
  QVVWNEYAEANWNYNTNITTETSKILLQKNMQIANHTLKYGTQARKFDVNQLQNTTIKRI
  IKKVQDLERAALPAQELEEYNKILLDMETTYSVATVCHPNGSCLQLEPDLTNVMATSRKY
  EDLLWAWEGWRDKAGRAILQFYPKYVELINQAARLNGYVDAGDSWRSMYETPSLEQDLER
  LFQELQPLYLNLHAYVRRALHRHYGAQHINLEGPIPAHLLGNMWAQTWSNIYDLVVPFPS
  APSMDTTEAMLKQGWTPRRMFKEADDFFTSLGLLPVPPEFWNKSMLEKPTDGREVVCHAS
  AWDFYNGKDFRIKQCTTVNLEDLVVAHHEMGHIQYFMQYKDLPVALREGANPGFHEAIGD
  VLALSVSTPKHLHSLNLLSSEGGSDEHDINFLMKMALDKIAFIPFSYLVDQWRWRVFDGS
  ITKENYNQEWWSLRLKYQGLCPPVPRTQGDFDPGAKFHIPSSVPYIRYFVSFIIQFQFHE
  ALCQAAGHTGPLHKCDIYQSKEAGQRLATAMKLGFSRPWPEAMQLITGQPNMSASAMLSY
  FKPLLDWLRTENELHGEKLGWPQYNWTPNSARSEGPLPDSGRVSFLGLDLDAQQARVGQW
  LLLFLGIALLVATLGLSQRLFSIRHRSLHRHSHGPQFGSEVELRHS
• 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. Composed of two similar catalytic domains, each possessing a functional active site, with different selectivity for substrates. 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. Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response. Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins. Catalyzes degradation of different enkephalin neuropeptides (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe and possibly Met-enkephalin-Arg-Gly-Leu). 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. Met-enkephalin-Arg-Phe cleavage by ACE decreases activation of OPRM1, leading to long-term synaptic potentiation of glutamate release. Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1. Involved in amyloid-beta metabolism by catalyzing degradation of Amyloid-beta protein 40 and Amyloid-beta protein 42 peptides, thereby preventing plaque formation. Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones. 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 ; [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. In contrast to somatic isoforms, only contains one catalytic domain. Acts as a dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of substrates. The identity of substrates that are needed for male fertility is unknown. 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. This activity is however unclear and has been challenged by other groups, suggesting that it may be indirect.
• 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.
• KEGG Pathway:
  Renin-angiotensin system (hsa04614)
  Renin secretion (hsa04924)
  Chagas disease (hsa05142)
  Coro.virus disease - COVID-19 (hsa05171)
  Hypertrophic cardiomyopathy (hsa05410)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway: Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)
• BioCyc Pathway: MetaCyc:HS08412-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute kidney injury	DISXZG0T	Definitive	Therapeutic	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[3]
Arrhythmia	DISFF2NI	Strong	Biomarker	[4]
Autism	DISV4V1Z	Strong	Genetic Variation	[5]
Brain ischaemia	DIS9Q4RT	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[7]
Gaucher disease type I	DIS87KKY	Strong	Biomarker	[8]
Gaucher disease type II	DISCI8IV	Strong	Biomarker	[8]
Gaucher disease type III	DISJFH8S	Strong	Biomarker	[8]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[9]
Glomerulosclerosis	DISJF20Z	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[12]
Hypotension	DISYNSM9	Strong	Therapeutic	[13]
Lung neoplasm	DISVARNB	Strong	Biomarker	[2]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[14]
Osteoporosis	DISF2JE0	Strong	Biomarker	[15]
Pre-eclampsia	DISY7Q29	Strong	Genetic Variation	[16]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[17]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[18]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[19]
Pulmonary hypertension	DIS1RSP5	Strong	Genetic Variation	[20]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[21]
Renal tubular dysgenesis	DISZ2OFK	Strong	Genetic Variation	[22]
Renal tubular dysgenesis of genetic origin	DISIP4Y5	Strong	Autosomal recessive	[23]
Ventricular fibrillation	DIS7IN76	Strong	Biomarker	[24]
Viral pneumonia	DISENI5X	Strong	Biomarker	[25]
Bipolar depression	DISA75FU	moderate	Biomarker	[26]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[27]
Gaucher disease	DISTW5JG	moderate	Biomarker	[28]
Glycogen storage disease V	DISJNC0O	moderate	Genetic Variation	[29]
Staphylococcus aureus infection	DISK6PTH	moderate	Biomarker	[30]
Staphylococcus infection	DISY8WGS	moderate	Biomarker	[30]
Coeliac disease	DISIY60C	Limited	Biomarker	[31]
Familial Alzheimer disease	DISE75U4	Limited	Biomarker	[32]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[33]
Gastric neoplasm	DISOKN4Y	Limited	Genetic Variation	[34]
Intracerebral hemorrhage	DISC81BT	Limited	Unknown	[35]
Meningococcal disease	DISGDM2Z	Limited	Altered Expression	[36]
Non-alcoholic fatty liver disease	DISDG1NL	Limited	Biomarker	[37]

This DOT Affected the Drug Response of 11 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Angiotensin-converting enzyme (ACE) affects the response to substance of Aspirin.	[52]
Phenylephrine	DMZHUO5	Approved	Angiotensin-converting enzyme (ACE) affects the response to substance of Phenylephrine.	[53]
Metoprolol	DMOJ0V6	Approved	Angiotensin-converting enzyme (ACE) affects the response to substance of Metoprolol.	[54]
Perindopril	DMOPZDT	Approved	Angiotensin-converting enzyme (ACE) affects the response to substance of Perindopril.	[55]
Fosinopril	DM9NJ52	Approved	Angiotensin-converting enzyme (ACE) increases the Blood pressure decreased ADR of Fosinopril.	[56]
Fluvastatin	DM4MDJY	Approved	Angiotensin-converting enzyme (ACE) increases the Lipids abnormal ADR of Fluvastatin.	[56]
Trandolapril	DM4L6EU	Approved	Angiotensin-converting enzyme (ACE) increases the Blood pressure decreased ADR of Trandolapril.	[56]
Cilazapril	DM4V6JA	Approved	Angiotensin-converting enzyme (ACE) affects the response to substance of Cilazapril.	[57]
Quinapril	DMR8H31	Approved	Angiotensin-converting enzyme (ACE) increases the Blood pressure decreased ADR of Quinapril.	[56]
Sildenafil	DM4YDAJ	Phase 3 Trial	Angiotensin-converting enzyme (ACE) increases the response of Sildenafil.	[58]
Ramipril	DM2R68E	Phase 2 Trial	Angiotensin-converting enzyme (ACE) increases the shorter time to lowering of blood pressure ADR of Ramipril.	[59]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Angiotensin-converting enzyme (ACE).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Angiotensin-converting enzyme (ACE).	[46]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Angiotensin-converting enzyme (ACE).	[39]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Angiotensin-converting enzyme (ACE).	[40]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Angiotensin-converting enzyme (ACE).	[41]
Cocaine	DMSOX7I	Approved	Cocaine increases the activity of Angiotensin-converting enzyme (ACE).	[42]
Cenestin	DMXQS7K	Approved	Cenestin decreases the activity of Angiotensin-converting enzyme (ACE).	[43]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Angiotensin-converting enzyme (ACE).	[44]
ORE-1001	DM471ZH	Phase 1/2	ORE-1001 decreases the activity of Angiotensin-converting enzyme (ACE).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Angiotensin-converting enzyme (ACE).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Angiotensin-converting enzyme (ACE).	[48]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Angiotensin-converting enzyme (ACE).	[49]
Edetic acid	DM10D85	Investigative	Edetic acid decreases the activity of Angiotensin-converting enzyme (ACE).	[50]
Lisinopril	DMUOK4C	Investigative	Lisinopril decreases the activity of Angiotensin-converting enzyme (ACE).	[51]

References

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