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Neuropeptidases

The term "neuropeptidases" refers to those enzymes that participate in the inactivation of synaptically released neuropeptides and therefore serve to turn off the generated peptide signal. In general, these enzymes are integral plasma membrane proteinases located as ectoenzymes. Some of the enzymes listed in the accompanying Tables are able to hydrolyze neuropeptides, but are present as cytosolic or secreted enzymes, or not present as ectoenzymes. Their physiological roles are therefore not fully established.

Only a relatively small group of CNS peptidases have been characterized as neuropeptide-inactivating ectoenzymes. The majority are zinc metalloenzymes for which specific and potent inhibitors have generally been developed. Some of these are found in abundance elsewhere, especially the renal and intestinal brush border membrane, but others appear to be more specific to the nervous system, e.g. pyroglutamyl aminopeptidase II. Neprilysin (NEP) is the prototype neuropeptidase originally discovered in the CNS as an enkephalin-degrading activity and subsequently as a substance P-hydrolyzing enzyme. It is appropriately located on neuronal membranes especially in the striatonigral pathway. Thus, it can act in an analogous manner to that of acetylcholinesterase at cholinergic terminals. Like several other neuropeptidases, it is also present in cells of the immune system where it may hydrolyze immunoregulatory peptides. In vivo, NEP is a broadly specific enzyme hydrolyzing a wide range of susceptible peptide substrates (enkephalins, substance P, atrial natriuretic peptide) as is its close homolog NEP II or secreted endopeptidase (SEP). Some other neuropeptidases appear to be much more substrate-specific. For example, pyroglutamyl amino-peptidase II appears to hydrolyze thyrotropin releasing hormone (TRH) exclusively. The unusual peptidase, glutamate carboxypeptidase II (GCP II) specifically inactivates the peptide neurotransmitter, N-acetylaspartylglutamate (NAAG) and GCP II inhibition can protect against some forms of neuronal death and may have applications in treatment of neuropathy.

Studies of changes in levels of neuropeptides in neurological disease have been limited in extent and no consistent pattern yet emerges. Likewise, factors regulating the expression of neuropeptidases both in the normal and the pathological state in the nervous system are little explored. Inhibitors of neuropeptidases are useful both as pharmacological tools in studies of neuropeptide physiology and also as potential therapeutic agents. Selective inhibitors of these enzymes have, to date, been obtained from natural products (e.g. phosphoramidon as NEP and endothelin converting enzyme 2 inhibitor) or designed (e.g. thiorphan selective for NEP) by analogy with similar enzymes from bacterial or other sources (e.g. thermolysin). Dual peptidase inhibitors (e.g. of NEP and angiotensin converting enzyme (ACE)) are increasingly finding favor as potential new therapeutics). Design of ACE, NEP and neurolysin inhibitors, in particular, will be aided by their recently solved three-dimensional structures.

A particular role for several neuropeptidases (especially NEP) has recently emerged in the turnover of the amyloidogenic Ab-peptide in Alzheimer's disease and age-dependent loss of NEP in the brain may contribute to the pathology. Strategies to up-regulate these CNS peptidases may therefore prove beneficial but raises some concerns with regard to potential side effects of their chronic inhibition.

Genome sequencing studies reveal that there are probably 8-10 NEP-like enzymes in the human genome and 24 in Drosophila. The Tables below describe the best characterized neuropeptidases. This includes a novel homolog of angiotensin converting enzyme (ACE2), not inhibited by classical ACE inhibitors, which appears to counterbalance the actions of ACE through its ability to convert angiotensin II to angiotensin-(1-7). Like several ectopeptidases, ACE2 serves serendipitously as a viral receptor, in this case for the severe acute respiratory syndrome (SARS) virus.

The Tables below contain accepted modulators and additional information. For a list of additional products, see the Related Products section below.

Endopeptidases

NameNeprilysin
(EC 3.4.24.11)
Thimet oligopeptidase (T7705)
(EC 3.4.24.15)
Neurolysin
(EC 3.4.24.16)
Prolyl oligopeptidase (O9515)
(EC 3.4.21.26)
Alternate NameEndopeptidase-24.11
Neutral endopeptidase
Enkephalinase
CALLA
CD10
Endopeptidase-24.15
Endo-oligopeptidase A
Endopeptidase-24.16
NT degrading endopeptidase
Oligopeptidase M
Post-proline cleaving enzyme
TRH deamidating enzyme
Typical
Substrates
In vitro
Leu- (L9133) and Met-Enkephalin (M6638)
ANP (A1663 (h), /HU/enA8208 (r))
ET-1 (E7764)
ET-2 (E9012)
ET-3 (E9137)
CCK (C2175)
NT (N6383)
SS (S9129S1763)
SP (S6883)
NKA (N4267)
NKB (N4143)
Amyloid β-peptide
AI (A9650 (h))
AII (A9525 (h))
BK (B3259)
LHRH (L7134 (h), L4897 (s))
NT (N6383)
SS (S9129, S1763)
Nociceptin/Orphanin FQ (O4011)
AI (A9650 (h))
AII (A9525 (h))
BK (B3259)
NT (N6383)
SP (S6883)
SS (S9129S1763)
AI (A9650 (h))
AII (A9525 (h))
BK (B3259)
LHRH (L7134 (h), L4897 (s))
NT (N6383)
SP (S6883)
TRH (P1319)
Vasopressin (V0377)
Oxytocin (O3251O4375)
Proteinase ClassMetallo (Zn2+)Metallo (Zn2+)Metallo (Zn2+)Serine
Typical InhibitorsPhosphoramidon (R7385)
Thiorphan (T6031)
CPP-Ala-Ala-Tyr-pAB
CPE-Ala-Ala-Phe-pAB
Phosphodiepryl 21
CPP-Ala-Ala-Tyr-pAB
CPE-Ala-Ala-Phe-pAB
Phosphodiepryl 21
Cbz-Pro-Prolinal
Subcellular
Localization
Plasma membraneSoluble and membrane
Nuclear
Soluble, plasma membrane, (mitochondrial)Soluble
Tissue
Distribution
Kidney
Intestine
Lung
Reproductive tissue
Brain
Ubiquitous, esp. testisKidney
Brain
Liver
Kidney
Brain
Liver
Physiological
Effects
Blood pressure
Pain regulation
Anti-inflammatory
Antidiarrhoeic
Vascular physiology
Reproductive physiology
Immune surveillance
Modulation of neurotensin physiologyLearning and memory
Peptide digestion
Disease
Relevance
Cardiovascular, cancer (esp. prostate)
Alzheimer's disease
Hypertension Cognitive disorders
Neurological disease

Aminopeptidases

NameAminopeptidase N
(EC 3.4.11.2)
Aminopeptidase A
(EC 3.4.11.7)
Aminopeptidase B
(EC 3.4.11.6)
Aminopeptidase P
(EC 3.4.11.9)
Alternate NameAminopeptidase M
CD13 membrane alanyl aminopeptidase
Aspartate or glutamyl
Aminopeptidase
Angiotensinase A
BPI/6C3 antigen
Arylamidase II
Arginine-aminopeptidase
X-Pro aminopeptidase
Aminopeptidase P
Typical
Substrates
In vitro
Leu-Enkephalin (L9133)
Met-Enkephalin (M6638)
γ- and β-endorphin
(E6261 (h), E0637 (b), E1142 (r))
AIII
AI (A9650 (h))
AII (A9525 (h))
CCK8
Leu-Enkephalin (L9133)
Met-Enkephalin (M6638)
BK (B3259)
LTA4 (L5170)
SRIF (S9129)
BK (B3259)
SP (S6883)
PYY (P1306 (h), P5801 (p))
Enterostatin (E2643 (h))
NPY (N5017 (h), N3266 (p), N6269 (sh))
Proteinase ClassMetallo (Zn2+)Metallo (Zn2+)Metallo (Zn2+)
Thiol Cl- activated
Metallo (Zn2+)
Typical InhibitorsAmastatin (A1276)
Bestatin (B8385)
Actinonin (A6671)
PC18
Amastatin (A1276),
 EC33
Arphamenine A
Arphamenine B
Bestatin (B8385)
Lysine thiol
Apstatin
Subcellular
Localization
Plasma membranePlasma membraneSoluble, secreted, GolgiPlasma membrane, GPI-anchored, cytosolic
Tissue
Distribution
Abundant in kidney, intestine, liver,
placenta, brain, lung, hematopoietic (myeloid) cells,
vascular and endothelial cells
Lung, kidney, placenta, intestine,
brain, hematopoietic cells, endothelial and epithelial cells
Widely distributed, esp. kidney, intestine,
lung, heart, brain, pituitary,
pancreas, testis
Kidney, liver, intestine, lung,
serum, vascular endothelial cells, hematopoietic cells
Physiological
Effects
Pain regulation, T-cell development, angiogenesis,
viral receptor (coronavirus 229E),
glutathione metabolism
Blood pressure regulation,
tumor progression/metastasis
InflammationPeptide digestion,
blood pressure regulation
Disease
Relevance
Cancer
Metastasis
Hypertension
Cancer
Autoimmune disease
Inflammatory disordersCardiovascular disease
NameDipeptidylpeptidase IV (D7052D4943D3446)
(EC 3.4.14.5)
Pyroglutamyl aminopeptidase II
(EC 3.4.19.6)
Tripeptidyl peptidase III
Alternate NamePost-proline dipeptidyl aminopeptidase
CD26
gp110
TRH degrading ectoenzymeCCK degrading enzyme
Typical
Substrates
In vitro
SP (S6883)
PYY (P1306 (h), P5801 (p))
NPY (N5017 (h), N3266 (p), N6269 (sh))
Enterostatin (E2643 (h))
Glucagon-like peptide-1 (G3265 (h)) (incretins)
Glucagons (G1774)
TRH (P1319)CCK (C2175)
Proteinase ClassSerineMetallo (Zn2+)Serine
Typical InhibitorsDiprotin A (I9759)
Diprotin B
Glp-Asn-Pro-Tyr-Trp-AMCButabindide
Subcellular
Localization
Plasma membranePlasma membranePlasma membrane, cytosol
Tissue
Distribution
Kidney, small intestine, liver,
placenta, hematopoietic cells
Brain, pituitary, retina, lung, liverLiver, brain, gut, erythrocytes
Physiological
Effects
Digestion, regulation of proliferation and
differentiation of lymphocytes,
regulation of glucose metabolism
Regulation of pituitary hormone secretionObesity

Carboxypeptidases

NameNAALA dipeptidase
(EC 3.4.17.21)
Carboxypeptidase H
(EC 3.4.17.10)
Carboxypeptidase N
(EC 3.4.17.3)
Alternate NameNAAG hydrolase
Prostate-specific membrane antigen (PSMA)
Glutamate carboxypeptidase II
Carboxypeptidase E
Enkephalin convertase
Kininase I
Arginine carboxypeptidase
Typical
Substrates
In vitro
NAAG (A5930)Enkephalin hexapeptides
Dynorphin (1-13) (D7017)
BK (B3259)
Atriopeptin II (/HU/enA9035)
Enkephalin hexapeptides
Dynorphin (1-13) (D7017)
BK (B3259)
Atriopeptin II (/HU/enA9035)
Proteinase ClassMetalloMetalloMetallo (Zn2+)
Typical InhibitorsQuisqualate (Q2128)GEMSA
MGTA
MGTA
Subcellular
Localization
Plasma membraneMembrane, secretory vesiclesSoluble
Tissue
Distribution
Brain, intestine, prostate, kidneyBrain, pituitary, pancreas, neuroendocrine tissuesLiver, blood (stomach, kidney, lung)
Physiological
Effects
Regulation of glutamate metabolismNeuroendocrine physiology, pancreatic physiology,
muscle strength/co-ordination
Protection against anaphylaxis
Disease
Relevance
Neuroprotection
Schizophrenia
Prostate cancer (marker)
Obesity
Diabetes
Obesity
Diabetes
NameCarboxypeptidase P
(EC 3.4.16.2
Peptidyl dipeptidase A (A2580A6778)
(EC 3.4.15.1)
Angiotensin converting enzyme-2 (SRP8000)
Alternate NameProlylcarboxypeptidase
Angiotensinase C
Pro-X carboxypeptidase
Angiotensin I-converting enzyme
Kininase II
ACE2 (ACEH)
Typical
Substrates
In vitro
AII (A9525 (h))
[des-Arg9]-bradykinin enterostatin (E2643 (h))
AI (A9650 (h))
BK (B3259)
CCK (C2175)
Gastrin (G9020 (h), G1276 (r))
Leu- (L9133) and Met-Enkephalin (M6638)
Ac-Ser-Asp-Lys-Pro (hemoregulatory peptide)
NT (N6383)
LH-RH (L8008L4897)
Substance P (S6883)
AI (A9650 (h), A2928 (s))
AII (A9525 (h))
[des-Arg9]-bradykinin
NT (N6383)
Proteinase ClassSerineMetallo (Zn2+)Metallo (Zn2+)
Typical InhibitorsZ-Pro-ProlinalCaptopril (C4042)
Lisinopril (L6292)
Enalaprilat (616958)
EDTA (ED2SS)
MLN-4760
Subcellular
Localization
LysosomalPlasma membrane, soluble (plasma)Plasma membrane, soluble (plasma)
Tissue
Distribution
Brain, heart, placenta, lung, liver,
skeletal muscle, kidney, pancreas,
leukocytes, vascular endothelial cells
Lung, kidney, testis, intestine, brain, endothelial cells, bloodKidney, heart, testis, intestine
Physiological
Effects
Inflammation, vasoregulationCardiovascular regulation, fertility,
water and salt balance, hematopoietic stem cell proliferation
Cardiac physiology, receptor for SARS virus,
fat uptake/metabolism
Disease
Relevance
Septic shockHypertension
Congestive heart failure
Diabetes
Nephropathy
Renal insufficiency
Cardiovascular disease
Obesity
Diabetes
SARS

Abbreviations

AI: Angiotensin I
AII: Angiotensin II
AIII: Angiotensin III
AMC: 7-Amido-4-methyl coumarin
ANP: Atrial natriuretic peptide
BK: Bradykinin
CALLA: Common acute lymphoblastic leukemia antigen
CCK: Cholecystokinin
CD: Cluster differentiation antigen
CPE: Carboxy-phenyl ethyl
CPP: Carboxy-phenyl propyl
EDTA: Ethylenediaminetetraacetic acid
EC33: (S)-3-Amino-4-mercaptobutyl sulfonic acid
ET-I: Endothelin-1
ET-2: Endothelin-2
ET-3: Endothelin-3
GEMSA: Guanidinoethylmercaptosuccinic acid
Glp: Pyroglutamyl
GPI: Glycosylphosphatidylinositol
LHRH: Luteinizing hormone-releasing hormone
MGTA: 2-Mercaptomethyl-3-guanidinoethylthiopropranoic acid
MLN: (S,S)-2-[1-Carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino]-4-methylpentanoic acid)
NAAG: N-Acetyl-L-aspartyl-L-glutamate
NAALA: N-Acetylated a-linked acidic dipeptidase
NKA: Neurokinin A
NKB: Neurokinin B
NPY: Neuropeptide Y
NT: Neurotensin
PC18: 2-Amino-4-methylsulfonyl butane thiol
PYY: Peptide YY
SARS: Severe acute respiratory syndrome
SP: Substance P
SRIF: Somatostatin
SS: Somatostatin
TRH: Thyrotropin releasing hormone

b: bovine
h: human
p: porcine
r: rat
s: salmon
sh: sheep

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References

1.
Acharya KR, Sturrock ED, Riordan JF, Ehlers MRW. 2003. Ace revisited: A new target for structure-based drug design. Nat Rev Drug Discov. 2(11):891-902. https://doi.org/10.1038/nrd1227
2.
Woessner JF, Barrett AJ, Rawlings ND. 2004. Handbook of Proteolytic Enzymes. [Internet]. Amsterdam: 2nd Ed., Vols 1 & 2, Elsevier/Academic Press, Amsterdam. Available from: https://www.sciencedirect.com/book/9780120796113/handbook-of-proteolytic-enzymes#book-description
3.
Berent-Spillson A, Robinson AM, Golovoy D, Slusher B, Rojas C, Russell JW. 2004. Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3. J Neurochem. 89(1):90-99. https://doi.org/10.1111/j.1471-4159.2003.02321.x
4.
2013. Correction to: ?A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme?. Pharmacol Rev. 65(1):544-544. https://doi.org/10.1124/pr.111.01er13
5.
Broder C, Becker-Pauly C. 2013. The metalloproteases meprin ? and meprin ?: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis. 450(2):253-264. https://doi.org/10.1042/bj20121751
6.
Brown CK, Madauss K, Lian W, Beck MR, Tolbert WD, Rodgers DW. 2001. Structure of neurolysin reveals a deep channel that limits substrate access. Proceedings of the National Academy of Sciences. 98(6):3127-3132. https://doi.org/10.1073/pnas.051633198
7.
Carson JA, Turner AJ. ?-Amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases?. 81(1):1-8. https://doi.org/10.1046/j.1471-4159.2002.00855.x
8.
Carter RE, Feldman AR, Coyle JT. 1996. Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase.. Proceedings of the National Academy of Sciences. 93(2):749-753. https://doi.org/10.1073/pnas.93.2.749
9.
Facchinetti P, Rose C, Schwartz J, Ouimet T. 2003. Ontogeny, regional and cellular distribution of the novel metalloprotease neprilysin 2 in the rat: a comparison with neprilysin and endothelin-converting enzyme-1. Neuroscience. 118(3):627-639. https://doi.org/10.1016/s0306-4522(02)01002-3
10.
Hoyer D, Bartfai T. 2012. Neuropeptides and Neuropeptide Receptors: Drug Targets, and Peptide and Non-Peptide Ligands: a Tribute to Prof.Dieter Seebach. Chemistry & Biodiversity. 9(11):2367-2387. https://doi.org/10.1002/cbdv.201200288
11.
Mizutani S, Wright JW, Kobayashi H. 2011. Placental Leucine Aminopeptidase- and Aminopeptidase A- Deficient Mice Offer Insight concerning the Mechanisms Underlying Preterm Labor and Preeclampsia. Journal of Biomedicine and Biotechnology. 20111-12. https://doi.org/10.1155/2011/286947
12.
Oefner C, D?Arcy A, Hennig M, Winkler FK, Dale GE. 2000. Structure of human neutral endopeptidase (neprilysin) complexed with phosphoramidon 1 1Edited by R. Huber. Journal of Molecular Biology. 296(2):341-349. https://doi.org/10.1006/jmbi.1999.3492
13.
Reaux A, Fournie-Zaluski MC, David C, Zini S, Roques BP, Corvol P, Llorens-Cortes C. 1999. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proceedings of the National Academy of Sciences. 96(23):13415-13420. https://doi.org/10.1073/pnas.96.23.13415
14.
Schank J, Ryabinin A, Giardino W, Ciccocioppo R, Heilig M. 2012. Stress-Related Neuropeptides and Addictive Behaviors: Beyond the Usual Suspects. Neuron. 76(1):192-208. https://doi.org/10.1016/j.neuron.2012.09.026
15.
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. 2000. A Human Homolog of Angiotensin-converting Enzyme. J. Biol. Chem.. 275(43):33238-33243. https://doi.org/10.1074/jbc.m002615200
16.
Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, et al. 2004. ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis. J. Biol. Chem.. 279(17):17996-18007. https://doi.org/10.1074/jbc.m311191200
17.
Turner AJ, Hiscox JA, Hooper NM. 2004. ACE2: from vasopeptidase to SARS virus receptor. Trends in Pharmacological Sciences. 25(6):291-294. https://doi.org/10.1016/j.tips.2004.04.001
18.
Wang W, Bodiga S, Das SK, Lo J, Patel V, Oudit GY. 2012. Role of ACE2 in diastolic and systolic heart failure. Heart Fail Rev. 17(4-5):683-691. https://doi.org/10.1007/s10741-011-9259-x
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