M28: Aminopeptidase Y | Enzymes | IUPHAR/BPS Guide to PHARMACOLOGY

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M28: Aminopeptidase Y C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Enzymes

1608

Folate hydrolase 1B Show summary »« Hide summary

Target Id	1607
Nomenclature	Folate hydrolase 1B
Previous and unofficial names	FOLH2 \| FOLHP \| GCPIII \| PSMAL \| folate hydrolase 2 \| glutamate carboxypeptidase III \| prostate specific membrane antigen like protein \| folate hydrolase 1B
Genes	FOLH1B (Hs)
Ensembl ID	ENSG00000134612 (Hs)
UniProtKB AC	Q9HBA9 (Hs)

Folate hydrolase (prostate-specific membrane antigen) 1 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1606

Nomenclature

Folate hydrolase (prostate-specific membrane antigen) 1

Previous and unofficial names

Genes

FOLH1 (Hs), Folh1 (Mm), Folh1 (Rn)

Ensembl ID

ENSG00000086205 (Hs), ENSMUSG00000001773 (Mm), ENSRNOG00000013770 (Rn)

UniProtKB AC

Q04609 (Hs), O35409 (Mm), P70627 (Rn)

EC number

3.4.17.21

Inhibitors

vipivotide tetraxetan pK_i 9.4 [2]

Antibodies

capromab (Binding)

Comment

Folate hydrolase is also known as NAALADase as it is responsible for the hydrolysis of N-acetaspartylglutamate to form N-acetylaspartate and L-glutamate (L-glutamic acid). In the gut, the enzyme assists in the assimilation of folate by hydrolysing dietary poly-gamma-glutamylfolate. The enzyme is highly expressed in the prostate, and its expression is up-regulated in cancerous tissue. A tagged version of the antibody capromab has been used for imaging purposes.

glutaminyl-peptide cyclotransferase Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2411

Nomenclature

glutaminyl-peptide cyclotransferase

Previous and unofficial names

GCT | glutaminyl cyclase | glutaminyl-tRNA cyclotransferase | QC | secretory glutaminyl cyclase (sQC)

Genes

QPCT (Hs), Qpct (Mm), Qpct (Rn)

Ensembl ID

ENSG00000115828 (Hs), ENSMUSG00000024084 (Mm), ENSRNOG00000005705 (Rn)

UniProtKB AC

Q16769 (Hs), Q9CYK2 (Mm)

EC number

2.3.2.5

Comment

This glutaminyl cyclase is a soluble enzyme (soluble QC, or sQC) that catalyses post-translational pyroglutamation (cyclization of N-terminal glutamine) of substrate proteins such as CCL2 (CCL2, P13500) and CX₃CL1 (CX3CL1, P78423) and a number of neuroendocrine peptides (e.g. TRH (TRH, P20396) and GnRH I (GNRH1, P01148)) [8]. Pyroglutamation is known to enhance protein stability and bioactive conformation, and dysregulated pyroglutamation has been associated with human diseases, including neurodegeneratrive diseases and cancer [5-6,10,12]. Selective inhibitors are proposed to reduce post-translational pyroglutamate modification of amyloid-β that is associated with amyloid-β neurotoxicity [4].

glutaminyl-peptide cyclotransferase like Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3289

Nomenclature

glutaminyl-peptide cyclotransferase like

Previous and unofficial names

Golgi QC (gQC) | isoQC

Genes

QPCTL (Hs), Qpctl (Mm), Qpctl (Rn)

Ensembl ID

ENSG00000011478 (Hs), ENSMUSG00000030407 (Mm), ENSRNOG00000015413 (Rn)

UniProtKB AC

Q9NXS2 (Hs), Q9D8T5 (Mm)

EC number

2.3.2.5

Endogenous substrates

CCL7

CCL2

CX₃CL1

Inhibitors

BI-43 pIC₅₀ 7.4 [9]

Comment

The QPCTL gene encodes a glutaminyl cyclase (QC) that is tethered to the Golgi membrane (referred to in the literature as gQC or isoQC). It is a functional isozyme of the soluble QC encoded by the QPCT gene and like sQC it catalyses post-translational pyroglutamation (cyclization of N-terminal glutamine) of substrate proteins. Comparison of X-ray structures of the catalytic domains of sQC and gQC suggest that the isoforms have distinct substrate selectivities [7]. Notably, gQC is required for the pyroglutamate modification of CD47 that is essential for facilitating the CD47/SIRPαα interaction which mediates the 'don't eat me' signal. Pyroglutamation is known to enhance protein stability and bioactive conformation, and dysregulated pyroglutamation has been associated with human diseases, including neurodegeneratrive diseases and cancer [1,3,5-6,10,12]. Both sQC and gQC are druggable targets for the development of selective inhibitors with therapeutic potential [11].

N-Acetylated α-linked acidic dipeptidase-like 1 Show summary »« Hide summary

Target Id

1608

Nomenclature

N-Acetylated α-linked acidic dipeptidase-like 1

Previous and unofficial names

ileal peptidase I100 | 100 kDa ileum brush border membrane protein | ileal dipeptidylpeptidase | NAALADase L

Genes

NAALADL1 (Hs), Naaladl1 (Mm), Naaladl1 (Rn)

Ensembl ID

ENSG00000168060 (Hs), ENSMUSG00000054999 (Mm), ENSRNOG00000021000 (Rn)

UniProtKB AC

Q9UQQ1 (Hs), Q7M758 (Mm), O54697 (Rn)

EC number

3.4.17.21

N-Acetylated α-linked acidic dipeptidase 2 Show summary »« Hide summary More detailed page go icon to follow link

Comments

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References

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1. Barreira da Silva R, Leitao RM, Pechuan-Jorge X, Werneke S, Oeh J, Javinal V, Wang Y, Phung W, Everett C, Nonomiya J et al.. (2022) Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. Nat Immunol, 23 (4): 568-580. [PMID:35314846]

2. Benešová M, Schäfer M, Bauder-Wüst U, Afshar-Oromieh A, Kratochwil C, Mier W, Haberkorn U, Kopka K, Eder M. (2015) Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. J Nucl Med, 56 (6): 914-20. [PMID:25883127]

3. Bresser K, Logtenberg MEW, Toebes M, Proost N, Sprengers J, Siteur B, Boeije M, Kroese LJ, Schumacher TN. (2022) QPCTL regulates macrophage and monocyte abundance and inflammatory signatures in the tumor microenvironment. Oncoimmunology, 11 (1): 2049486. [PMID:35309731]

4. Chen D, Chen Q, Qin X, Tong P, Peng L, Zhang T, Xia C. (2023) Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease. Front Aging Neurosci, 15: 1209863. [PMID:37600512]

5. Coimbra JR, Sobral PJ, Santos AE, Moreira PI, Salvador JA. (2019) An overview of glutaminyl cyclase inhibitors for Alzheimer's disease. Future Med Chem, 11 (24): 3179-3194. [PMID:31838899]

6. Coimbra JRM, Moreira PI, Santos AE, Salvador JAR. (2023) Therapeutic potential of glutaminyl cyclases: Current status and emerging trends. Drug Discov Today, 28 (10): 103644. [PMID:37244566]

7. Huang KF, Liaw SS, Huang WL, Chia CY, Lo YC, Chen YL, Wang AH. (2011) Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. J Biol Chem, 286 (14): 12439-49. [PMID:21288892]

8. Kehlen A, Haegele M, Böhme L, Cynis H, Hoffmann T, Demuth HU. (2017) N-terminal pyroglutamate formation in CX3CL1 is essential for its full biologic activity. Biosci Rep, 37 (4). [PMID:28739588]

9. Mou J, Ning XL, Wang XY, Hou SY, Meng FB, Zhou C, Wu JW, Li C, Jia T, Wu X et al.. (2024) X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model. J Med Chem, 67 (11): 8730-8756. [PMID:38817193]

10. Van Manh N, Hoang VH, Ngo VTH, Ann J, Jang TH, Ha JH, Song JY, Ha HJ, Kim H, Kim YH et al.. (2021) Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design. Eur J Med Chem, 226: 113819. [PMID:34536669]

11. Yu L, Zhao P, Sun Y, Zheng Z, Du W, Zhang L, Li Y, Xie L, Xu S, Wang P. (2023) Development of a potent benzonitrile-based inhibitor of glutaminyl-peptide cyclotransferase-like protein (QPCTL) with antitumor efficacy. Signal Transduct Target Ther, 8 (1): 454. [PMID:38097557]

12. Zhang Y, Wang Y, Zhao Z, Peng W, Wang P, Xu X, Zhao C. (2022) Glutaminyl cyclases, the potential targets of cancer and neurodegenerative diseases. Eur J Pharmacol, 931: 175178. [PMID:35948163]

How to cite this family page

Database page citation:

M28: Aminopeptidase Y. Accessed on 24/06/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=748.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.

M28: Aminopeptidase Y C

Enzymes

Comments

Further reading

References

How to cite this family page