ACE

Summary

ACE (angiotensin I converting enzyme, HGNC:2707) is a protein-coding gene on chromosome 17q23.3, encoding Angiotensin-converting enzyme (P12821). 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.

This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer’s disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms.

Source: NCBI Gene 1636 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal tubular dysgenesis - ACE (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 40
• Clinical variants (ClinVar): 849 total — 30 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes — 31 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000789

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2707
Approved symbol	ACE
Name	angiotensin I converting enzyme
Location	17q23.3
Locus type	gene with protein product
Status	Approved
Aliases	ACE1, CD143
Ensembl gene	ENSG00000159640
Ensembl biotype	protein_coding
OMIM	106180
Entrez	1636

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 15 protein_coding, 6 retained_intron, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000290863, ENST00000290866, ENST00000413513, ENST00000428043, ENST00000577418, ENST00000578679, ENST00000578839, ENST00000579204, ENST00000579314, ENST00000579462, ENST00000579726, ENST00000580318, ENST00000582005, ENST00000582244, ENST00000582627, ENST00000582678, ENST00000582761, ENST00000583336, ENST00000583645, ENST00000584529, ENST00000584865, ENST00000884274, ENST00000884275, ENST00000884276, ENST00000884277, ENST00000884278, ENST00000884279, ENST00000884280, ENST00000884281, ENST00000953328

RefSeq mRNA: 6 — MANE Select: NM_000789 NM_000789, NM_001178057, NM_001382700, NM_001382701, NM_001382702, NM_152830

CCDS: CCDS11637, CCDS45755, CCDS54155

Canonical transcript exons

ENST00000290866 — 25 exons

Exon	Start	End
ENSE00002259849	63497137	63498373
ENSE00003460790	63488941	63489132
ENSE00003484452	63479007	63479100
ENSE00003485879	63490954	63491051
ENSE00003498519	63482466	63482689
ENSE00003545829	63493922	63494066
ENSE00003546645	63485236	63485372
ENSE00003548315	63483029	63483173
ENSE00003557946	63496798	63496985
ENSE00003561256	63486986	63487073
ENSE00003566846	63484330	63484541
ENSE00003574324	63493436	63493659
ENSE00003583833	63483849	63483971
ENSE00003606637	63488648	63488791
ENSE00003629718	63477061	63477343
ENSE00003644850	63491209	63491381
ENSE00003655430	63479769	63479912
ENSE00003657193	63480337	63480528
ENSE00003659350	63486557	63486715
ENSE00003661262	63477931	63478098
ENSE00003665301	63483460	63483558
ENSE00003666007	63481566	63481738
ENSE00003673106	63481091	63481188
ENSE00003683947	63494372	63494470
ENSE00003685583	63496394	63496516

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 98.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6907 / max 1168.7492, expressed in 923 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162181	4.9983	854
162182	0.1968	81
162189	0.1637	4
162180	0.1434	59
162195	0.0425	4
208311	0.0361	10
162190	0.0283	3
162184	0.0200	6
162191	0.0197	3
162192	0.0168	4

Top tissues by expression

260 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.92	gold quality
right testis	UBERON:0004534	97.07	gold quality
left testis	UBERON:0004533	96.93	gold quality
jejunal mucosa	UBERON:0000399	95.08	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.19	gold quality
small intestine	UBERON:0002108	93.01	gold quality
mucosa of transverse colon	UBERON:0004991	92.80	gold quality
testis	UBERON:0000473	92.13	gold quality
duodenum	UBERON:0002114	91.96	gold quality
upper lobe of left lung	UBERON:0008952	90.70	gold quality
apex of heart	UBERON:0002098	90.34	gold quality
right uterine tube	UBERON:0001302	89.84	gold quality
upper lobe of lung	UBERON:0008948	88.82	gold quality
right lung	UBERON:0002167	88.22	gold quality
adenohypophysis	UBERON:0002196	85.78	gold quality
gall bladder	UBERON:0002110	84.64	gold quality
right lobe of thyroid gland	UBERON:0001119	84.53	gold quality
left lobe of thyroid gland	UBERON:0001120	84.18	gold quality
thyroid gland	UBERON:0002046	84.00	gold quality
lung	UBERON:0002048	83.90	gold quality
transverse colon	UBERON:0001157	83.23	gold quality
putamen	UBERON:0001874	83.17	gold quality
caudate nucleus	UBERON:0001873	82.72	gold quality
pituitary gland	UBERON:0000007	82.68	gold quality
smooth muscle tissue	UBERON:0001135	82.42	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.28	gold quality
ectocervix	UBERON:0012249	82.25	gold quality
omental fat pad	UBERON:0010414	81.43	gold quality
peritoneum	UBERON:0002358	81.32	gold quality
intestine	UBERON:0000160	81.07	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	725.04
E-ANND-3	yes	7.80
E-GEOD-111727	no	50.83
E-MTAB-6142	no	34.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
GJA1	Repression

Upstream regulators (CollecTRI, top): AP1, ATF2, CEBPA, CREM, EGR1, ETS1, FOXC1, HIF1A, JUN, KLF2, MYC, NR3C2, POU4F2, PPARA, PPARG, SP3, SRY

miRNA regulators (miRDB)

49 targeting ACE, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628

Literature-anchored findings (GeneRIF, showing 16)

• The DD genotype of ACE polymorphism is a risk factor for coronary artery disease and coronary stent restenosis in Japanese patients. (PMID:11665795)
• During shedding of the ectodomain of ACE, a minimum requirement is an exposed or unhindered sequence of minimum length between the extracellular domain and the membrane, within or adjacent to otherwise compact, folded domains. (PMID:11747437)
• association between left ventricular hypertrophy and the C825T allele of the G-protein beta3 subunit gene in Arabs. (G PROTEIN BETA3) (PMID:11768721)
• It appears that the DD genotype (of ACE gene) is associated with progression of Japanese type 2 diabetic nephropathy. (PMID:11770799)
• vasomotor properties are influenced by the I/D polymorphism of the ACE gene. (PMID:11818755)
• ACE insertion/deletion polymorphism and submaximal exercise cardiovascular hemodynamics in postmenopausal women. (PMID:11842043)
• Homozygosity for the insertion allele of the I/D polymorphism is associated with adaptation to high altitude. (PMID:11851983)
• ACE polymorphism is not a risk factor for the development of cerebral infarction in a Korean population. (PMID:11859923)
• effects of monoclonal antibodies (mAbs) to eight different epitopes on the N-terminal domain of ACE on shedding (PMID:11879185)
• alleles of the ACE gene may be a predisposing factor for developing white matter lesions in essential hypertensive patients. (PMID:11882570)
• Angiotensin I-converting enzyme and metabolism of the haematological peptide N-acetyl-seryl-aspartyl-lysyl-proline. (PMID:11903317)
• Different aortic reflection wave responses following long-term angiotensin-converting enzyme inhibition and beta-blocker in essential hypertension (PMID:11903319)
• A prospective evaluation of the angiotensin-converting enzyme D/I polymorphism and left ventricular remodeling in the ‘Healing and Early Afterload Reducing Therapy’ study. (PMID:11903350)
• Toward an optimal joint recognition of the S1’ subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). (PMID:11906289)
• Polymorphisms of genes encoding kininase II as risk factors for orthostatic hypotension. (PMID:11910300)
• Enhanced responses of blood pressure, renal function, and aldosterone to angiotensin I in the DD genotype are blunted by low sodium intake. MAP, renal hemodynamic parameters, and aldosterone concentrations to AngI are enhanced for DD genotype. (PMID:11912262)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ace	ENSMUSG00000020681
rattus_norvegicus	Ace	ENSRNOG00000062101

Paralogs (1): ACE2 (ENSG00000130234)

Protein

Protein identifiers

Angiotensin-converting enzyme — P12821 (reviewed: P12821)

Alternative names: Dipeptidyl carboxypeptidase I, Kininase II

All UniProt accessions (9): P12821, A0A0A0MSN4, J3KRH5, J3KS28, J3KSQ5, J3KTB8, J3KTH9, J3QLR4, J3QSC7

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Monomer and homodimer; homodimerizes following binding to an inhibitor. Interacts with calmodulin (CALM1, CALM2 or CALM3); interaction takes place in the cytoplasmic region and regulates phosphorylation and proteolytic cleavage.

Subcellular location. Cell membrane. Cytoplasm Secreted Cell membrane. Secreted.

Tissue specificity. Ubiquitously expressed, with highest levels in lung, kidney, heart, gastrointestinal system and prostate. Specifically expressed in spermatocytes and adult testis.

Post-translational modifications. Produced following proteolytic cleavage by secretase enzymes that cleave the transmembrane form in the juxtamembrane stalk region upstream of the transmembrane region. Cleavage can take place at different sites of the juxtamembrane stalk region. Phosphorylated by CK2 on Ser-1299; which allows membrane retention. Phosphorylated on tyrosine residues on its extracellular part, promoting cleavage by secretase enzymes and formation of the soluble form (Angiotensin-converting enzyme, soluble form).

Disease relevance. Ischemic stroke (ISCHSTR) [MIM:601367] 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. Disease susceptibility is associated with variants affecting the gene represented in this entry. Renal tubular dysgenesis (RTD) [MIM:267430] 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). The disease is caused by variants affecting the gene represented in this entry. Microvascular complications of diabetes 3 (MVCD3) [MIM:612624] 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. Disease susceptibility is associated with variants affecting the gene represented in this entry. 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. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. The dipeptidyl carboxypeptidase activity is strongly activated by chloride. The dipeptidyl carboxypeptidase activity is specifically inhibited by lisinopril, captopril and enalaprilat. Strongly inhibited by lisinopril and captopril.

Cofactor. Binds 2 Zn(2+) ions per subunit. Isoform Testis-specific only binds 1 Zn(2+) ion per subunit. Binds 3 chloride ions per subunit.

Induction. Up-regulated in failing heart.

Miscellaneous. Inhibitors of ACE are commonly used to treat hypertension and some types of renal and cardiac dysfunction. Incomplete sequence.

Similarity. Belongs to the peptidase M2 family.

Isoforms (4)

UniProt ID	Names	Canonical?
P12821-1	Somatic-1	yes
P12821-2	Somatic-2, Soluble
P12821-3	Testis-specific, ACE-T, ACEt, tACE, hTACE
P12821-4	4

RefSeq proteins (6): NP_000780, NP_001171528, NP_001369629, NP_001369630, NP_001369631, NP_690043 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001548	Peptidase_M2	Family

Pfam: PF01401

Enzyme classification (BRENDA):

• EC 3.4.15.1 — peptidyl-dipeptidase A (BRENDA: 31 organisms, 224 substrates, 941 inhibitors, 246 Km, 169 kcat entries)

Substrate kinetics (BRENDA)

95 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HIPPURYL-HIS-LEU	0.0308–20	30
ANGIOTENSIN I	0.009–2.7	25
BENZYLOXYCARBONYL-PHE-HIS-LEU	0.13–2.8	8
BENZOYL-GLY-HIS-LEU	0.56–18.2	4
LEQIYHL	0.0157–0.4125	4
LVVYPWTQRY	0.014–0.033	4
N-(3-(2-FURYL)ACRYLOYL)-PHE-PHE-ARG	0.05–0.12	4
NKLKPSQWI	0.0147–0.5237	4
NKLKPSQWISL	0.0027–0.1505	4
NKLKPSQWISLSD	0.1367–0.6738	4
[PHE9,ARG10]ANGIOTENSIN I	0.011–0.025	4
2-FURANACRYLOYL-PHE-GLY-GLY	0.08–0.174	3
HIPPURYL-PHE-ARG	0.5–1.8	3
N-(3-(2-FURYL)ACRYLOYL)-PHE-ALA-LYS	0.14–0.17	3
N-(3-(2-FURYL)ACRYLOYL)-PHE-ALA-PRO	0.005–0.008	3

Catalyzed reactions (Rhea), 10 shown:

• angiotensin I + H2O = L-histidyl-L-leucine + angiotensin II (RHEA:63560)
• Met-enkephalin-Arg-Phe + H2O = L-arginyl-L-phenylalanine + Met-enkephalin (RHEA:70675)
• bradykinin + H2O = L-Phe-L-Arg + bradykinin(1-7) (RHEA:71451)
• goralatide + H2O = N-acetyl-L-seryl-L-aspartate + L-lysyl-L-proline (RHEA:71455)
• substance P + H2O = substance P(1-9) + L-Leu-L-Met-NH2 (RHEA:71459)
• substance P + H2O = substance P(1-8) + Gly-L-Leu-L-Met-NH2 (RHEA:71463)
• substance P + H2O = L-Phe-L-Phe-Gly-L-Leu-L-Met-NH2 + substance P(1-6) (RHEA:71471)
• neurotensin + H2O = neurotensin(1-11) + L-isoleucyl-L-leucine (RHEA:71475)
• Met-enkephalin + H2O = L-phenylalanyl-L-methionine + L-tyrosylglycylglycine (RHEA:71483)
• Leu-enkephalin + H2O = L-tyrosylglycylglycine + L-phenylalanyl-L-leucine (RHEA:71487)

UniProt features (212 total): helix 64, sequence variant 24, mutagenesis site 23, strand 20, glycosylation site 20, binding site 16, turn 13, disulfide bond 6, splice variant 6, active site 4, site 4, chain 2, topological domain 2, domain 2, sequence conflict 2, signal peptide 1, modified residue 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

97 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6H5W	X-RAY DIFFRACTION	1.37
9H1E	X-RAY DIFFRACTION	1.45
7Q27	X-RAY DIFFRACTION	1.5
9QAN	X-RAY DIFFRACTION	1.5
9QAP	X-RAY DIFFRACTION	1.5
5AMB	X-RAY DIFFRACTION	1.55
6F9T	X-RAY DIFFRACTION	1.6
7Q25	X-RAY DIFFRACTION	1.6
7Q29	X-RAY DIFFRACTION	1.6
8QFX	X-RAY DIFFRACTION	1.6
5AMC	X-RAY DIFFRACTION	1.65
7Q28	X-RAY DIFFRACTION	1.65
6F9V	X-RAY DIFFRACTION	1.69
6TT3	X-RAY DIFFRACTION	1.7
7Q26	X-RAY DIFFRACTION	1.7
9H1B	X-RAY DIFFRACTION	1.7
6EN5	X-RAY DIFFRACTION	1.75
7Z6Z	X-RAY DIFFRACTION	1.75
4C2O	X-RAY DIFFRACTION	1.8
4UFA	X-RAY DIFFRACTION	1.8
4UFB	X-RAY DIFFRACTION	1.8
5AM9	X-RAY DIFFRACTION	1.8
5AMA	X-RAY DIFFRACTION	1.8
6EN6	X-RAY DIFFRACTION	1.8
6H5X	X-RAY DIFFRACTION	1.8
6QS1	X-RAY DIFFRACTION	1.8
6TT1	X-RAY DIFFRACTION	1.8
6TT4	X-RAY DIFFRACTION	1.8
9H1C	X-RAY DIFFRACTION	1.8
9H1D	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12821-F1	91.38	0.82

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (8): 520 (proton donor 1); 989 (proton acceptor 2); 1118 (proton donor 2); 523 (not glycosylated); 1166–1167 (cleavage); 1225 (not glycosylated); 1232–1233 (cleavage); 391 (proton acceptor 1)

Ligand- & substrate-binding residues (16): 231; 390; 394; 418; 529; 791; 829; 414; 418; 442; 988; 992 …

Post-translational modifications (1): 1299

Disulfide bonds (6): 157–165, 359–377, 545–557, 757–763, 957–975, 1143–1155

Glycosylation sites (20): 103, 121, 140, 368, 617, 38, 54, 74, 111, 146, 160, 318, 445, 509, 677, 695, 714, 760, 942, 1191

Mutagenesis-validated functional residues (23):

Position	Phenotype
103	in ace(t)g0 mutant; abolished n-glycosylation leading to impaired stability and degradation; when associated with d-121,
121	in ace(t)g0 mutant; abolished n-glycosylation leading to impaired stability and degradation; when associated with d-103,
140	in ace(t)g0 mutant; abolished n-glycosylation leading to impaired stability and degradation; when associated with d-103,
368	in ace(t)g0 mutant; abolished n-glycosylation leading to impaired stability and degradation; when associated with d-103,
553	abolished binding to chloride ion.
617	in ace(t)g0 mutant; abolished n-glycosylation leading to impaired stability and degradation; when associated with d-103,
318	in ndom123456 mutant; abolished dipeptidyl carboxypeptidase activity; when associated with d-445 and d-509. in ndom12345
390–394	abolished dipeptidyl carboxypeptidase activity; when associated with 988-k–k-992. abolished n-terminal active sites, le
391	abolished peptidase activity, leading to increased levels of amyloid-beta; when associated with d-989.
445	in ndom123456 mutant; abolished dipeptidyl carboxypeptidase activity; when associated with d-318 and d-445. in ndom12345
509	in ndom123456 mutant; abolished dipeptidyl carboxypeptidase activity; when associated with d-318 and d-445.
529	abolished dependence to chloride, leading to reduced peptidyl dipeptidase activity.
988–992	abolished dipeptidyl carboxypeptidase activity; when associated with 390-k–k-394. abolishes the second active site, pre
989	abolished peptidase activity, leading to increased levels of amyloid-beta; when associated with d-391.
1016	strongly decreased dipeptidyl carboxypeptidase activity; when associated with 390-k–k-394.
1016	abolished dipeptidyl carboxypeptidase activity; when associated with 390-k–k-394.
1020	decreased dipeptidyl carboxypeptidase activity; when associated with 390-k–k-394.
1116	decreased ability to cleave substance p and bradykinin. reduced binding to captopril inhibitor.
1125	decreased ability to cleave substance p and captopril inhibitor.
1127	abolished dependence to chloride, leading to reduced peptidyl dipeptidase activity.
1166	does not prevent cleavage and secretion of the soluble form, suggesting that processing can take place at different site
1229	increased cleavage and secretion of the soluble form by generating a new cleavage site.
1299	abolishes phosphorylation and decreases membrane retention.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 318 (showing top): MODULE_172, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, MODULE_255, GOBP_RESPONSE_TO_ANGIOTENSIN, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, MODULE_317, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, KYNG_DNA_DAMAGE_DN, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY

GO Biological Process (36): kidney development (GO:0001822), blood vessel remodeling (GO:0001974), angiotensin maturation (GO:0002003), regulation of renal output by angiotensin (GO:0002019), neutrophil mediated immunity (GO:0002446), antigen processing and presentation of peptide antigen via MHC class I (GO:0002474), regulation of systemic arterial blood pressure by renin-angiotensin (GO:0003081), positive regulation of systemic arterial blood pressure (GO:0003084), proteolysis (GO:0006508), spermatogenesis (GO:0007283), regulation of blood pressure (GO:0008217), male gonad development (GO:0008584), post-transcriptional regulation of gene expression (GO:0010608), negative regulation of gene expression (GO:0010629), substance P catabolic process (GO:0010814), bradykinin catabolic process (GO:0010815), regulation of smooth muscle cell migration (GO:0014910), regulation of vasoconstriction (GO:0019229), mononuclear cell proliferation (GO:0032943), angiotensin-activated signaling pathway (GO:0038166), hormone metabolic process (GO:0042445), hormone catabolic process (GO:0042447), peptide catabolic process (GO:0043171), regulation of synaptic plasticity (GO:0048167), amyloid-beta metabolic process (GO:0050435), arachidonate secretion (GO:0050482), heart contraction (GO:0060047), regulation of angiotensin metabolic process (GO:0060177), hematopoietic stem cell differentiation (GO:0060218), cell proliferation in bone marrow (GO:0071838), regulation of heart rate by cardiac conduction (GO:0086091), blood vessel diameter maintenance (GO:0097746), regulation of hematopoietic stem cell proliferation (GO:1902033), negative regulation of gap junction assembly (GO:1903597), maintenance of blood vessel diameter homeostasis by renin-angiotensin (GO:0002034), vasodilation (GO:0042311)

GO Molecular Function (20): actin binding (GO:0003779), endopeptidase activity (GO:0004175), metallocarboxypeptidase activity (GO:0004181), metalloendopeptidase activity (GO:0004222), calmodulin binding (GO:0005516), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), exopeptidase activity (GO:0008238), tripeptidyl-peptidase activity (GO:0008240), peptidyl-dipeptidase activity (GO:0008241), zinc ion binding (GO:0008270), chloride ion binding (GO:0031404), mitogen-activated protein kinase kinase binding (GO:0031434), bradykinin receptor binding (GO:0031711), mitogen-activated protein kinase binding (GO:0051019), metallodipeptidase activity (GO:0070573), carboxypeptidase activity (GO:0004180), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), lysosome (GO:0005764), endosome (GO:0005768), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide hormone metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	3
cellular anatomical structure	3
regulation of gene expression	2
metalloexopeptidase activity	2
exopeptidase activity	2
protein kinase binding	2
animal organ development	1
renal system development	1
tissue remodeling	1
regulation of angiotensin levels in blood	1
peptide hormone processing	1
regulation of blood volume by renin-angiotensin	1
myeloid leukocyte mediated immunity	1
antigen processing and presentation of peptide antigen	1
regulation of systemic arterial blood pressure by hormone	1
regulation of systemic arterial blood pressure	1
positive regulation of blood pressure	1
protein metabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
blood circulation	1
regulation of biological quality	1
gonad development	1
development of primary male sexual characteristics	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
neuropeptide catabolic process	1
catabolic process	1
smooth muscle cell migration	1
regulation of cell migration	1
vasoconstriction	1
blood vessel diameter maintenance	1
regulation of blood circulation	1
leukocyte proliferation	1
G protein-coupled receptor signaling pathway	1
cellular response to angiotensin	1
cytoskeletal protein binding	1
carboxypeptidase activity	1
endopeptidase activity	1
metallopeptidase activity	1

Protein interactions and networks

STRING

3622 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACE	AGT	P01019	990
ACE	REN	P00797	987
ACE	AGTR1	P30556	975
ACE	KNG1	P01042	960
ACE	ACE2	Q9BYF1	953
ACE	AGTR2	P50052	949
ACE	ALB	P02768	912
ACE	NR3C2	P08235	892
ACE	MMEL1	Q495T6	889
ACE	BDKRB2	P30411	884
ACE	MME	P08473	883
ACE	CRP	P02741	878
ACE	BDKRB1	P46663	875
ACE	APOE	P02649	875
ACE	DPP4	P27487	872

IntAct

9 interactions, top by confidence:

A	B	Type	Score
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530
DDX6	MCRIP1	psi-mi:“MI:0914”(association)	0.510
PLK4	SF3B1	psi-mi:“MI:0914”(association)	0.350
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
TEX101	ACE	psi-mi:“MI:0914”(association)	0.350
METTL9	SLC27A2	psi-mi:“MI:0914”(association)	0.350
CD247	RSL1D1	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): ACE (Proximity Label-MS), ACE (Proximity Label-MS), ACE (Proximity Label-MS), ACE (Proximity Label-MS), ACE (Affinity Capture-MS), ACE (Affinity Capture-MS), ACE (Affinity Capture-MS), ACE (Affinity Capture-MS), ACE (Affinity Capture-MS), ACE (Cross-Linking-MS (XL-MS)), CLCN3 (Co-fractionation), LNPEP (Co-fractionation), ALMS1 (Co-fractionation), ITGB7 (Co-fractionation), NBEAL1 (Co-fractionation)

ESM2 similar proteins: A0A0B4K692, B2RQR8, D0G895, F1N476, F1RRW5, M3XFH7, O16796, O44857, O95672, P07861, P08049, P08473, P09470, P0C1T0, P0DPD6, P0DPD8, P0DPD9, P0DPE2, P12820, P12821, P12822, P23276, P42891, P42892, P42893, P47820, P97629, P97739, Q07075, Q18673, Q22523, Q495T6, Q4PZA2, Q50JE5, Q5RE69, Q5RFP3, Q61391, Q6P179, Q6Q4G3, Q8C129

Diamond homologs: D0G895, F1RRW5, P09470, P12820, P12821, P12822, P47820, Q10714, Q10715, Q10751, Q50JE5, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RFN1, Q6Q4G4, Q8R0I0, Q9BYF1, Q9GLN7, Q9VLJ6, Q0VCT4, Q9ESG3, Q9ESG4, Q9HBJ8

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
ACE	“up-regulates activity”	AGT	cleavage
ACE	“down-regulates quantity by destabilization”	bradykinin	binding
benazepril	“down-regulates activity”	ACE	“chemical inhibition”
Angiotensin-1	“up-regulates activity”	ACE	binding
ACE	“up-regulates quantity”	Angiotensin-2	cleavage
trandolapril	“down-regulates activity”	ACE	“chemical inhibition”
enalapril	“down-regulates activity”	ACE	“chemical inhibition”
“enalaprilat (anhydrous)”	“down-regulates activity”	ACE	“chemical inhibition”
ramipril	“down-regulates activity”	ACE	“chemical inhibition”
lisinopril	“down-regulates activity”	ACE	“chemical inhibition”
captopril	“down-regulates activity”	ACE	“chemical inhibition”
fosinoprilat	“down-regulates activity”	ACE	“chemical inhibition”
CSNK2A1	“up-regulates activity”	ACE	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

849 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	29
Uncertain significance	426
Likely benign	183
Benign	72

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028377	NM_000789.4(ACE):c.1744C>T (p.Gln582Ter)	Pathogenic
1285167	NM_000789.4(ACE):c.870G>A (p.Trp290Ter)	Pathogenic
1285224	NM_000789.4(ACE):c.2673_2674dup (p.Tyr892fs)	Pathogenic
1320127	NM_000789.4(ACE):c.1454dup (p.Ser486fs)	Pathogenic
1456190	NM_000789.4(ACE):c.1292del (p.Pro431fs)	Pathogenic
18064	NM_000789.4(ACE):c.1319_1322del (p.Leu440fs)	Pathogenic
1908262	NM_000789.4(ACE):c.833dup (p.Ala279fs)	Pathogenic
235336	NM_000789.4(ACE):c.1522C>T (p.Arg508Ter)	Pathogenic
2506013	NM_000789.4(ACE):c.3409C>T (p.Gln1137Ter)	Pathogenic
2573840	NM_000789.4(ACE):c.793C>T (p.Arg265Ter)	Pathogenic
2631754	NM_000789.4(ACE):c.3503+1G>A	Pathogenic
2688850	NM_000789.4(ACE):c.3272G>A (p.Trp1091Ter)	Pathogenic
2688857	NM_000789.4(ACE):c.3550C>T (p.Gln1184Ter)	Pathogenic
2712424	NM_000789.4(ACE):c.444_445insTTAGC (p.Arg149fs)	Pathogenic
2738638	NM_000789.4(ACE):c.3221G>A (p.Trp1074Ter)	Pathogenic
3250667	NM_000789.4(ACE):c.1499_1500del (p.Gln500fs)	Pathogenic
3391860	GRCh37/hg19 17q23.2-24.1(chr17:58773496-62757149)x3	Pathogenic
4085539	NM_000789.4(ACE):c.3281+1del	Pathogenic
4215261	NM_000789.4(ACE):c.51del (p.Leu18fs)	Pathogenic
424033	NM_000789.4(ACE):c.412C>T (p.Gln138Ter)	Pathogenic
4531674	NM_000789.4(ACE):c.207G>A (p.Trp69Ter)	Pathogenic
4685105	NM_000789.4(ACE):c.3430C>T (p.Gln1144Ter)	Pathogenic
50209	NM_000789.4(ACE):c.2371C>T (p.Arg791Ter)	Pathogenic
58702	GRCh37/hg19 17q23-24(chr17:59209629-64222315)x3	Pathogenic
625756	GRCh37/hg19 17q22-24.2(chr17:57357088-66306668)	Pathogenic
632285	NM_000789.4(ACE):c.2149_2150del (p.Ile717fs)	Pathogenic
827586	NM_000789.4(ACE):c.1473_1475delinsA (p.Asp491fs)	Pathogenic
974372	NM_000789.4(ACE):c.1361del (p.Leu454fs)	Pathogenic
974373	NM_000789.4(ACE):c.1384dup (p.Ile462fs)	Pathogenic
974413	NM_000789.4(ACE):c.899del (p.Phe300fs)	Pathogenic

SpliceAI

4724 predictions. Top by Δscore:

Variant	Effect	Δscore
17:63477341:CAGG:C	donor_loss	1.0000
17:63477342:AG:A	donor_loss	1.0000
17:63477343:GG:G	donor_loss	1.0000
17:63477344:G:GA	donor_loss	1.0000
17:63477345:T:A	donor_loss	1.0000
17:63477918:T:A	acceptor_gain	1.0000
17:63478084:GC:G	donor_gain	1.0000
17:63478085:C:G	donor_gain	1.0000
17:63478996:T:TA	acceptor_gain	1.0000
17:63479005:A:AG	acceptor_gain	1.0000
17:63479006:G:GA	acceptor_gain	1.0000
17:63479908:GGACG:G	donor_gain	1.0000
17:63479909:G:GT	donor_gain	1.0000
17:63480524:GCTGG:G	donor_gain	1.0000
17:63480527:GG:G	donor_gain	1.0000
17:63480527:GGGTA:G	donor_loss	1.0000
17:63480528:GG:G	donor_gain	1.0000
17:63480529:G:A	donor_loss	1.0000
17:63480529:G:GG	donor_gain	1.0000
17:63480530:T:G	donor_loss	1.0000
17:63481085:A:AG	acceptor_gain	1.0000
17:63481086:T:G	acceptor_gain	1.0000
17:63481087:CTAG:C	acceptor_loss	1.0000
17:63481089:A:AG	acceptor_gain	1.0000
17:63481089:AG:A	acceptor_gain	1.0000
17:63481090:G:GT	acceptor_gain	1.0000
17:63481090:GG:G	acceptor_gain	1.0000
17:63481090:GGA:G	acceptor_gain	1.0000
17:63481090:GGAGA:G	acceptor_gain	1.0000
17:63481184:AGCAG:A	donor_gain	1.0000

AlphaMissense

8613 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:63490974:T:A	W888R	0.998
17:63490974:T:C	W888R	0.998
17:63494053:T:A	W1090R	0.998
17:63494053:T:C	W1090R	0.998
17:63494056:T:A	W1091R	0.998
17:63494056:T:C	W1091R	0.998
17:63482476:T:A	C377S	0.997
17:63482476:T:C	C377R	0.997
17:63482477:G:C	C377S	0.997
17:63488701:T:A	W787R	0.997
17:63488701:T:C	W787R	0.997
17:63488703:G:C	W787C	0.997
17:63488703:G:T	W787C	0.997
17:63491381:G:C	R971P	0.997
17:63493446:T:A	C975S	0.997
17:63493447:G:C	C975S	0.997
17:63493572:G:C	A1017P	0.997
17:63493999:T:A	W1072R	0.997
17:63493999:T:C	W1072R	0.997
17:63494003:G:C	R1073P	0.997
17:63496829:T:A	W1179R	0.997
17:63496829:T:C	W1179R	0.997
17:63481111:T:A	W290R	0.996
17:63481111:T:C	W290R	0.996
17:63485328:T:A	W672R	0.996
17:63485328:T:C	W672R	0.996
17:63485330:G:C	W672C	0.996
17:63485330:G:T	W672C	0.996
17:63488714:G:C	R791P	0.996
17:63489127:T:C	L879P	0.996

dbSNP variants (sampled 300 via entrez): RS1000066436 (17:63487806 T>C), RS1000122167 (17:63488080 C>T), RS1000161428 (17:63493049 C>T), RS1000292458 (17:63482734 C>A,G,T), RS1000379624 (17:63498129 C>A,T), RS1000446893 (17:63491863 G>A), RS1000979672 (17:63477568 C>G,T), RS1001051825 (17:63477712 C>G), RS1001149523 (17:63497003 A>C,G), RS1001178750 (17:63495955 C>T), RS1001347873 (17:63490892 G>A,C), RS1001525772 (17:63481994 G>A), RS1001586554 (17:63485611 A>G), RS1001742109 (17:63486549 G>A,C,T), RS1001895327 (17:63480630 A>G)

Disease associations

OMIM: gene MIM:106180 | disease phenotypes: MIM:267430, MIM:612624, MIM:614519, MIM:601331, MIM:608446, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
renal tubular dysgenesis of genetic origin	Strong	Autosomal recessive
intracerebral hemorrhage	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
renal tubular dysgenesis - ACE	Definitive	AR

Mondo (10): renal tubular dysgenesis (MONDO:0017609), renal tubular dysgenesis of genetic origin (MONDO:0009970), microvascular complications of diabetes, susceptibility to, 3 (MONDO:0012963), hemorrhage, intracerebral, susceptibility to (MONDO:0100533), renal dysplasia, cystic, susceptibility to (MONDO:0011037), myocardial infarction, susceptibility to (MONDO:0012039), microcephaly (MONDO:0001149), hereditary angioedema with normal C1Inh (MONDO:0100567), congenital anomaly of kidney and urinary tract (MONDO:0019719), intracerebral hemorrhage (MONDO:0013792)

Orphanet (4): Renal tubular dysgenesis (Orphanet:3033), Renal tubular dysgenesis of genetic origin (Orphanet:97369), Hereditary angioedema with normal C1Inh (Orphanet:528647), Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000079	Abnormality of the urinary system
HP:0000252	Microcephaly
HP:0001562	Oligohydramnios
HP:0002009	Potter facies
HP:0002089	Pulmonary hypoplasia
HP:0002093	Respiratory insufficiency
HP:0002615	Hypotension
HP:0004492	Widely patent fontanelles and sutures
HP:0008660	Renotubular dysgenesis
HP:0100519	Anuria

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000565_2	Angiotensin-converting enzyme activity	3.000000e-25
GCST001217_23	Metabolic traits	8.000000e-20
GCST001882_9	Metabolite levels	9.000000e-13
GCST002245_33	Alzheimer’s disease (late onset)	3.000000e-07
GCST002388_1	Serum metabolite levels	9.000000e-25
GCST002388_3	Serum metabolite levels	1.000000e-18
GCST002388_4	Serum metabolite levels	8.000000e-14
GCST002665_1	Cerebrospinal fluid levels of Alzheimer’s disease-related proteins	4.000000e-12
GCST004280_7	Diastolic blood pressure	7.000000e-14
GCST004777_41	Diastolic blood pressure	2.000000e-07
GCST004777_69	Diastolic blood pressure	2.000000e-14
GCST006166_42	Diastolic blood pressure x alcohol consumption interaction (2df test)	1.000000e-12
GCST006190_5	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	7.000000e-16
GCST006190_74	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-13
GCST006192_60	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-12
GCST006192_76	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	6.000000e-14
GCST006193_38	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-16
GCST006193_76	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-14
GCST006195_38	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-13
GCST006195_70	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	8.000000e-15
GCST006249_101	Serum metabolite levels	1.000000e-16
GCST006249_102	Serum metabolite levels	4.000000e-14
GCST006249_103	Serum metabolite levels	5.000000e-15
GCST006249_104	Serum metabolite levels	3.000000e-12
GCST006249_25	Serum metabolite levels	1.000000e-11
GCST006434_70	Systolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-12
GCST006585_132	Blood protein levels	9.000000e-136
GCST007094_24	Diastolic blood pressure	4.000000e-08
GCST007099_106	Systolic blood pressure	1.000000e-08
GCST007267_245	Systolic blood pressure	1.000000e-09

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0006515	angiotensin-converting enzyme measurement
EFO:0006336	diastolic blood pressure
EFO:0004329	alcohol drinking
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:1001870	late-onset Alzheimers disease
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0009268	family history of Alzheimer’s disease

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002543	Cerebral Hemorrhage	C10.228.140.300.535.200; C14.907.253.573.200; C23.550.414.913.100
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C566906	Cakut (supp.)
C537755	Renal dysplasia diffuse cystic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL1808 (SINGLE PROTEIN), CHEMBL2096989 (PROTEIN FAMILY), CHEMBL6066541 (PROTEIN COMPLEX), CHEMBL6066554 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

31 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,741,651 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL1165	MOEXIPRIL	4	14,871
CHEMBL1168	RAMIPRIL	4	46,990
CHEMBL1237	LISINOPRIL ANHYDROUS	4	56,016
CHEMBL1422	SITAGLIPTIN	4	26,582
CHEMBL1519	TRANDOLAPRIL	4	20,506
CHEMBL1560	CAPTOPRIL	4	66,415
CHEMBL1581	PERINDOPRIL	4	22,987
CHEMBL1592	QUINAPRIL	4	31,043
CHEMBL191	LOSARTAN	4	88,932
CHEMBL3039598	FOSINOPRIL	4	61
CHEMBL317094	IMIDAPRIL	4	9,592
CHEMBL577	ENALAPRILAT ANHYDROUS	4	10,256
CHEMBL578	ENALAPRIL	4	52,784
CHEMBL838	BENAZEPRIL	4	28,085
CHEMBL858	EDETIC ACID	3	1,231,124
CHEMBL1192519	BENAZEPRILAT	2	2,671
CHEMBL1201405	MOEXIPRILAT	2	714
CHEMBL1733	QUINAPRILAT	2	3,766
CHEMBL289556	OMAPATRILAT	2	799
CHEMBL309962	RENTIAPRIL	2
CHEMBL331378	ZOFENOPRIL	2
CHEMBL36503	CERONAPRIL	2
CHEMBL408983	TEPROTIDE	2
CHEMBL42583	SAMPATRILAT	2
CHEMBL430554	LIBENZAPRIL	2
CHEMBL54922	PROLINE	2
CHEMBL579	SPIRAPRILAT	2
CHEMBL581	FOSINOPRILAT	2
CHEMBL99701	IMIDAPRILAT	2

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

27 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1799752	Efficacy	2A	captopril	Chronic Obstructive Pulmonary Disease;Diabetes Mellitus;Type 2;Heart Failure
rs1799752	Efficacy	3	fluoxetine;sertraline	Depressive Disorder
rs1799752	Efficacy	3	bumetanide;furosemide;torasemide
rs1799752	Efficacy	3	benazepril;perindopril	Diabetes Mellitus
rs1799752	Efficacy	3	hydrochlorothiazide	Essential hypertension
rs1799752	Efficacy	3	irbesartan	Hypertension;Hypertrophy;Left Ventricular
rs1799752	Efficacy	3	enalapril	Arteriosclerosis;Coronary Disease;Essential hypertension;Glomerulonephritis;IGA;Kidney Disorder
rs1799752	Efficacy	4	lisinopril	Diabetes Mellitus;Type 1;Heart Failure
rs1799752	Efficacy	3	nitroprusside
rs1799752	Efficacy	3	acetylcholine
rs1799752	Efficacy	3	spironolactone	Heart Failure
rs1799752	Efficacy	3	pravastatin
rs1799752	Efficacy	3	fluvastatin	Coronary Artery Disease
rs1799752	Efficacy	3	atorvastatin;quinapril	Coronary Artery Disease
rs1799752	Other	3	antidepressants;antiepileptics;Beta Blocking Agents;Calcium channel blockers	Headache Disorders;Migraine with Aura;Migraine without Aura
rs1799752	Toxicity	3	Ace Inhibitors;Plain
rs4291	Efficacy	3	amlodipine;chlorthalidone;lisinopril	Hypertension
rs4291	Toxicity	3	aspirin	Asthma
rs4291	Efficacy	3	captopril	Alzheimer Disease
rs4292	Toxicity	3	aspirin	Asthma
rs4341	Efficacy	3	pravastatin
rs4341	Toxicity	3	Thiazides;plain	Diabetes Mellitus
rs4343	Efficacy	3	sildenafil	Erectile Dysfunction
rs4343	Efficacy	3	spironolactone
rs4344	Efficacy	3	ramipril	Hypertension
rs4359	Efficacy	3	ramipril	Hypertension
rs8075924	Efficacy	3	bupropion	Major Depressive Disorder

PharmGKB variants

9 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4291	ACE	3	2.75	3	captopril;amlodipine;chlorthalidone;lisinopril;aspirin
rs4292	ACE	3	2.25	1	aspirin
rs4331	ACE		0.00	0
rs4341	ACE	3	2.75	2	Thiazides;plain;pravastatin
rs4343	ACE	3	2.50	2	sildenafil;spironolactone
rs4344	ACE	3	2.25	1	ramipril
rs4359	ACE	3	2.75	1	ramipril
rs4363	ACE		0.00	0
rs1799752	ACE	2A	13.00	16	spironolactone;atorvastatin;quinapril;enalapril;lisinopril;acetylcholine;nitroprusside;hydrochlorothiazide;fluvastatin;pravastatin;bumetanide;furosemide;torasemide

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M2: Angiotensin-converting enzymes (ACE and ACE2)

Most potent curated ligand interactions (24 total), top 24:

Ligand	Action	Affinity	Parameter
lisinopril	Inhibition	9.4	pKi
zofenoprilat	Inhibition	9.4	pKi
spiraprilat	Inhibition	9.1	pIC50
perindoprilat	Inhibition	9.0	pIC50
benazepril	Inhibition	8.8	pIC50
imidaprilat	Inhibition	8.7	pIC50
cilazaprilat	Inhibition	8.7	pIC50
quinaprilat	Inhibition	8.5	pIC50
trandolaprilat	Inhibition	8.5	pIC50
temocaprilat	Inhibition	8.44	pIC50
captopril	Inhibition	8.4	pKi
ramiprilat	Inhibition	8.4	pIC50
moexiprilat	Inhibition	8.2	pIC50
lisinopril-tryptophan	Inhibition	8.18	pIC50
RXP-407	Inhibition	8.15	pIC50
quinapril	Inhibition	8.1	pIC50
fosinoprilat	Inhibition	8.0	pIC50
fasidotrilat	Inhibition	8.0	pKi
trandolapril	Inhibition	7.8	pIC50
AD015	Inhibition	7.72	pIC50
ramipril	Inhibition	7.6	pIC50
enalaprilat	Inhibition	7.5	pIC50
benazeprilat	Inhibition	6.6	pIC50
enalapril	Inhibition	4.3	pIC50

Binding affinities (BindingDB)

10 measured of 12 human assays (13 total across all organisms); most potent 10 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
The second fraction of the HPLC chromatogram.	KI	0.13 nM
3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanoyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid	KI	0.4 nM
The second fraction of the HPLC chromatogram.	KI	0.7 nM
3-{1-(2-acetamido-4-methylpentanoyl)pyrrolidin-2-ylphosphoryl}-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid	KI	1.25 nM
RXP470, Compound 4	KI	192 nM
(2S)-2-[methyl-[(2S)-1-[(2S)-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]propanoic acid	IC50	640 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use
(4R)-5-amino-4-[[(2S)-4-carboxy-2-[3-[4-(4-phenylthiophen-2-yl)phenyl]propanoylamino]butanoyl]amino]-5-oxopentanoic acid	KI	1060 nM	US-8691753
(2R)-1-[(2S)-1-[(2S)-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxylic acid	IC50	12000 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use
(3S)-1-[(2S)-1-[(2S)-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-3-carboxylic acid	IC50	49000 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use
(3R)-1-[(2S)-1-[(2S,4S)-4-fluoro-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-3-carboxylic acid	IC50	68000 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use

ChEMBL bioactivities

853 potent at pChembl≥5 of 966 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.82	Ki	0.015	nM	OMAPATRILAT
10.80	Ki	0.016	nM	OMAPATRILAT
10.54	IC50	0.029	nM	CHEMBL443353
10.00	IC50	0.1	nM	LISINOPRIL ANHYDROUS
10.00	IC50	0.1	nM	OMAPATRILAT
9.96	IC50	0.11	nM	CHEMBL198316
9.94	IC50	0.1148	nM	CHEMBL35561
9.92	IC50	0.12	nM	CAPTOPRIL
9.88	IC50	0.1318	nM	CHEMBL35309
9.80	Ki	0.16	nM	CHEMBL1788109
9.74	IC50	0.18	nM	CHEMBL526298
9.70	Ki	0.2	nM	CHEMBL5931110
9.64	IC50	0.2291	nM	CHEMBL80665
9.60	IC50	0.2512	nM	CHEMBL78629
9.54	IC50	0.2884	nM	CHEMBL35682
9.53	IC50	0.2951	nM	CHEMBL284734
9.53	IC50	0.2951	nM	CHEMBL285935
9.50	Ki	0.316	nM	CHEMBL5848092
9.40	Ki	0.4	nM	CHEMBL570718
9.40	IC50	0.4	nM	ZOFENOPRIL
9.39	Ki	0.41	nM	CHEMBL570732
9.31	IC50	0.4898	nM	CHEMBL286339
9.30	Ki	0.5	nM	CHEMBL309601
9.30	Ki	0.501	nM	CHEMBL5872996
9.30	IC50	0.5	nM	CHEMBL295690
9.28	IC50	0.5248	nM	CHEMBL34832
9.28	IC50	0.5248	nM	CHEMBL289022
9.22	IC50	0.6	nM	CHEMBL340528
9.22	IC50	0.6026	nM	CHEMBL312224
9.22	IC50	0.6	nM	CHEMBL347755
9.20	IC50	0.63	nM	CAPTOPRIL
9.20	Ki	0.631	nM	CHEMBL5842509
9.20	IC50	0.631	nM	CHEMBL34650
9.19	Ki	0.65	nM	CHEMBL570953
9.17	Ki	0.68	nM	CHEMBL570953
9.15	IC50	0.7	nM	CHEMBL4476621
9.11	IC50	0.7762	nM	CHEMBL431707
9.10	IC50	0.8	nM	SPIRAPRILAT
9.10	IC50	0.7943	nM	CHEMBL110925
9.06	IC50	0.871	nM	CHEMBL33025
9.05	IC50	0.9	nM	CHEMBL499612
9.05	IC50	0.8913	nM	CHEMBL284843
9.03	IC50	0.93	nM	TRANDOLAPRIL
9.00	IC50	1	nM	CHEMBL95564
9.00	IC50	1	nM	OMAPATRILAT
9.00	Ki	1	nM	CHEMBL5750525
9.00	IC50	1	nM	CHEMBL315037
9.00	IC50	1	nM	FOSINOPRIL
9.00	IC50	1	nM	CHEMBL310750
9.00	IC50	1	nM	CHEMBL331575

PubChem BioAssay actives

676 with measured affinity, of 1402 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,5S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]-5-(3-phenylpropylsulfanyl)pyrrolidine-2-carboxylic acid	362193: Inhibition of ACE	ic50	<0.0001	uM
(4S,7S,12bR)-7-[[(1S)-1-carboxy-3-phenylpropyl]amino]-6-oxo-2,3,4,7,8,12b-hexahydro-1H-pyrido[2,1-a][2]benzazepine-4-carboxylic acid	1954028: Binding affinity to angiotensin-converting enzyme (unknown origin) assessed as inhibition constant	ki	<0.0001	uM
(4S,7S,10aS)-5-oxo-4-[[(2S)-3-phenyl-2-sulfanylpropanoyl]amino]-2,3,4,7,8,9,10,10a-octahydropyrido[2,1-b][1,3]thiazepine-7-carboxylic acid	1423287: Inhibition of human fully glycosylated ACE N-terminal domain expressed in CHO cells using Cbz-Phe-His-Leu as substrate preincubated for 15 mins followed by substrate addition measured after 10 mins by Morrison’s plot analysis	ki	<0.0001	uM
(2S,4R)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-4-phenylpyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0001	uM
2-[[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-(1,3-benzodioxol-5-yl)amino]acetic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0001	uM
Captopril	433785: Inhibition of human recombinant ACE by fluorimetry	ic50	0.0001	uM
(4R,7S)-6-oxo-7-[[(2R)-3-phenyl-2-sulfanylpropanoyl]amino]-2,3,4,7,8,12b-hexahydro-1H-pyrido[2,1-a][2]benzazepine-4-carboxylic acid	254756: Inhibitory concentration against angiotensin I converting enzyme	ic50	0.0001	uM
lisinopril anhydrous	1895844: Inhibition of angiotensin converting enzyme (unknown origin)	ic50	0.0001	uM
(2S)-1-[(2S)-2-[[1-carboxy-4-(4-iodoanilino)-4-oxobutyl]amino]propanoyl]pyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0002	uM
(2S,5S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]-5-(2-phenylethylsulfanyl)pyrrolidine-2-carboxylic acid	362193: Inhibition of ACE	ic50	0.0002	uM
(2S,4S,5R)-1-[(2R)-2-acetylsulfanylpropanoyl]-5-phenylpyrrolidine-2,4-dicarboxylic acid	38874: Enzyme inhibitory activity towards Angiotensin I converting enzyme	ki	0.0002	uM
2-[[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-cyclohexylamino]acetic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0003	uM
2-(N-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-3,4-dimethoxyanilino)acetic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0003	uM
(2S)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-2,3-dihydroindole-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0003	uM
(2S)-1-[(4R)-4-carboxy-4-[[3-phenyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]butanoyl]-2,3-dihydroindole-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0003	uM
(2S)-2-[[(2S)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]-3-phenylpropanoic acid	444546: Inhibition of human somatic ACE C-terminal domain	ki	0.0004	uM
(2S)-3-(4-hydroxyphenyl)-2-[[(2S)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]propanoic acid	444546: Inhibition of human somatic ACE C-terminal domain	ki	0.0004	uM
(2S,4S)-1-[(2S)-3-benzoylsulfanyl-2-methylpropanoyl]-4-phenylsulfanylpyrrolidine-2-carboxylic acid	39767: Inhibitory activity against angiotensin I converting enzyme (ACE)	ic50	0.0004	uM
(2S)-1-[(2S)-2-[[hydroxy(2-phenylethyl)phosphoryl]amino]propanoyl]pyrrolidine-2-carboxylic acid	38871: Compound was evaluated for the inhibition of Angiotensin I converting enzyme	ki	0.0005	uM
(8S)-7-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]hexanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid	38853: Compound tested in vitro for inhibition of Angiotensin I converting enzyme	ic50	0.0005	uM
(2S,4R)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-4-cyclohexylpyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0005	uM
(2S,4S)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-4-phenylsulfanylpyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0005	uM
(2S,4R)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-4-methylsulfanylpyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0005	uM
(2S)-3-(4-hydroxyphenyl)-2-[[(2R)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]propanoic acid	444546: Inhibition of human somatic ACE C-terminal domain	ki	0.0006	uM
(8S)-7-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0006	uM
(3R,9aR)-6-[(1-carboxy-3-phenylpropyl)amino]-5-oxo-3,6,7,8,9,9a-hexahydro-2H-[1,3]thiazolo[3,2-a]azepine-3-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0006	uM
(3R,6S)-6-[(1-carboxy-3-phenylpropyl)amino]-5-oxo-3,6,7,8,9,9a-hexahydro-2H-[1,3]thiazolo[3,2-a]azepine-3-carboxylic acid	38850: Inhibition of Angiotensin I converting enzyme	ic50	0.0006	uM
(3R,6S,9aR)-6-[(1-carboxy-3-phenylpropyl)amino]-5-oxo-3,6,7,8,9,9a-hexahydro-2H-[1,3]thiazolo[3,2-a]azepine-3-carboxylic acid	39622: Inhibition of Angiotensin I converting enzyme (ACE) in Bothrops jararaca venom	ic50	0.0006	uM
1-(3,4-dichlorophenyl)-3-[(2-hydroxybenzoyl)amino]thiourea	1584848: Inhibition of human recombinant ACE using Abz-FRK(Dnp)-P-OH as substrate after 30 mins by fluorimetric analysis	ic50	0.0007	uM
(2S,4R)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-4-phenylsulfanylpyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0008	uM
(8S)-7-[(2S)-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]propanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid	38853: Compound tested in vitro for inhibition of Angiotensin I converting enzyme	ic50	0.0008	uM
1-[2-[[1-carboxy-4-(4-iodoanilino)-4-oxobutyl]amino]propanoyl]pyrrolidine-2-carboxylic acid	38849: Inhibition of angiotensin I converting enzyme in silico	ic50	0.0008	uM
(2S,4S)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-4-benzylpyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0009	uM
(2S,4R)-1-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]-4-hydroxypyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0009	uM
(2S,5S)-5-[(3-methylphenyl)methylsulfanyl]-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid	362193: Inhibition of ACE	ic50	0.0009	uM
Trandolapril	39767: Inhibitory activity against angiotensin I converting enzyme (ACE)	ic50	0.0009	uM
(5S)-2-(2-carboxyethyl)-1,3-dioxo-5,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazine-5-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0010	uM
(2S)-1-[(2R,5S)-5-benzamido-2-methyl-4-oxo-6-phenylhexanoyl]pyrrolidine-2-carboxylic acid	39752: Inhibition of guinea pig serum Angiotensin I converting enzyme	ic50	0.0010	uM
6-methyl-1-(3-sulfanylpropanoyl)piperidine-2-carboxylic acid	39625: Inhibitory activity against Angiotensin I converting enzyme (ACE) from bovine kidney	ic50	0.0010	uM
Fosinopril	39767: Inhibitory activity against angiotensin I converting enzyme (ACE)	ic50	0.0010	uM
2-(N-[(2S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphoryl]oxyhexanoyl]anilino)acetic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0011	uM
(2S)-1-[(2S)-2-[(1-carboxy-3-naphthalen-1-ylpropyl)amino]propanoyl]pyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0011	uM
(2S)-1-[(2S)-2-[(1-carboxy-3-phenylpropyl)amino]propanoyl]pyrrolidine-2-carboxylic acid	39018: Inhibitory activity against angiotensin converting enzyme (ACE)	ic50	0.0012	uM
(4S,12bR)-7-[(1-carboxy-3-phenylpropyl)amino]-6-oxo-2,3,4,7,8,12b-hexahydro-1H-pyrido[2,1-a][2]benzazepine-4-carboxylic acid	38873: Compound was tested for its inhibitory potency against angiotensin I converting enzyme.	ki	0.0012	uM
enalaprilat dihydrate	1954024: Inhibition of angiotensin-converting enzyme (unknown origin)	ic50	0.0012	uM
(2S)-1-[(2S)-2-[[(2R)-2-carboxy-4-phenylbutan-2-yl]amino]propanoyl]pyrrolidine-2-carboxylic acid	38850: Inhibition of Angiotensin I converting enzyme	ic50	0.0012	uM
(2S)-3-(1H-indol-3-yl)-2-[[(2R)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-3-sulfanylpropanoyl]amino]propanoic acid	254288: Inhibition constant against angiotensin I converting enzyme	ki	0.0013	uM
(2S)-1-[5-benzamido-6-(3,4-dimethoxyphenyl)-4-oxohexanoyl]pyrrolidine-2-carboxylic acid	39754: Concentration required to inhibit the activity of Angiotensin I converting enzyme by 50%	ic50	0.0014	uM
(2S)-1-[5-(furan-2-carbonylamino)-4-oxo-6-phenylhexanoyl]pyrrolidine-2-carboxylic acid	39754: Concentration required to inhibit the activity of Angiotensin I converting enzyme by 50%	ic50	0.0014	uM
(2S)-2-[[(2S)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	444546: Inhibition of human somatic ACE C-terminal domain	ki	0.0014	uM

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
benazepril	affects response to substance, decreases activity	8
sodium arsenite	affects reaction, increases expression, affects binding, increases reaction, decreases expression (+1 more)	3
Enalapril	affects cotreatment, affects response to substance, decreases reaction, increases response to substance, decreases activity	3
Benzo(a)pyrene	decreases expression, increases methylation	2
Glucose	decreases reaction, increases expression, decreases expression	2
Tetradecanoylphorbol Acetate	decreases reaction, increases expression	2
Ramipril	decreases activity	2
Particulate Matter	decreases methylation, increases abundance, increases expression	2
ethylbenzene	decreases methylation, increases expression, affects cotreatment	1
lasiocarpine	decreases expression	1
bisphenol A	increases expression	1
zaprinast	increases expression, increases reaction	1
steviol	decreases expression	1
stevioside	decreases expression	1
bioallethrin	decreases activity	1
herbimycin	decreases reaction, increases expression	1
1,10-phenanthroline	decreases expression	1
rebaudioside A	decreases expression	1
boric acid	decreases activity, decreases reaction	1
epigallocatechin gallate	decreases activity, decreases reaction, affects binding	1
bisindolylmaleimide I	increases expression, decreases reaction	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases activity, affects cotreatment, affects localization	1
idrapril	decreases activity	1
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide	increases expression, increases reaction	1
nicotianamine	decreases activity	1
omapatrilat	decreases activity	1
2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid	decreases activity	1
ICG 001	decreases reaction, increases expression	1
Bortezomib	affects cotreatment, increases activity	1
Sunitinib	decreases expression	1

ChEMBL screening assays

304 unique, capped per target: 288 binding, 8 functional, 5 admet, 3 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002956	Binding	Inhibition of ACE	Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge. — Bioorg Med Chem
CHEMBL4269905	ADMET	Inhibition of human fully glycosylated ACE N-terminal domain expressed in CHO cells using Cbz-Phe-His-Leu as substrate preincubated for 15 mins followed by substrate addition measured after 10 mins by fluorescence spectrophotometric analysi	Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design. — J Med Chem
CHEMBL4406515	Unclassified	Selectivity index, ratio of Ki for human ACE N-domain soluble form (1 to 629 residues) expressed in CHO cells to Ki for human testis ACE C-domain lacking unique O-glycosylated region, transmembrane anchor and cytoplasmic tail expressed in C	Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin-Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C7SN	SK-N-FI ACE KO	Cancer cell line	Male
CVCL_F1RL	HyCyte MDA-MB-231 KO-hACE	Cancer cell line	Female
CVCL_SB19	HAP1 ACE (-) 1	Cancer cell line	Male
CVCL_SB20	HAP1 ACE (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

298 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00699465	PHASE4	UNKNOWN	Prevention of Venous Thromboembolism in Patients With Acute Primary Intracerebral Hemorrhage
NCT01918722	PHASE4	UNKNOWN	Clinical Re-evaluation of Removing Blood Stasis Therapy in Treating Acute Cerebral Hemorrhage Safety and Efficacy
NCT05095857	PHASE4	RECRUITING	The Anaesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury
NCT06429332	PHASE4	RECRUITING	International Care Bundle Evaluation in Cerebral Hemorrhage Research
NCT06673602	PHASE4	RECRUITING	Fufang Congrong Yizhi Capsules (FCYC) of Cognitive Impairment After Intracerebral Hemorrhage
NCT06899464	PHASE4	NOT_YET_RECRUITING	Safety and Feasibility of Using Cerebrolysin in the Treatment of Primary Intracerebral Hemorrhage - a Prospective Randomized Open Blinded End-point Trial
NCT07044232	PHASE4	NOT_YET_RECRUITING	NICardipine for Fast Achievement of Systolic BP Targets in ICH
NCT07609654	PHASE4	NOT_YET_RECRUITING	Oral Anticoagulation After Stroke With Prior ICH in Subjects With AF
NCT00127283	PHASE3	COMPLETED	Recombinant Factor VIIa in Acute Intracerebral Haemorrhage
NCT01176565	PHASE3	TERMINATED	Antihypertensive Treatment of Acute Cerebral Hemorrhage-II
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