The zinc form of carnosine dipeptidase 2 (CN2) has dipeptidase activity but its substrate specificity is different from that of the manganese form

Okumura, Nobuaki; Takao, Toshifumi

doi:10.1016/j.bbrc.2017.10.100

Cited by 6 publications

(3 citation statements)

References 26 publications

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“…Mammalian CNDP2 (also known as carnosine dipeptidase II, CN2, carboxypeptidase of glutamate-like, CPGL) belongs to the M20 family of metallopeptidases and has broad substrate specificity for dipeptides [1, 2]. It is active only as a homodimer [3], and the catalytic domain of each dimer subunit has one active center with two Mn 2+ or Zn 2+ ions, which determine the specificity of the enzyme for its physiological substrates [4]. So far, CNDP2 is the only known protease that can catalyze the formation of pseudodipeptides of lactic acid and amino acids ( N -lactoyl-amino acids) through reverse proteolysis in vivo [5].…”

Section: Introductionmentioning

confidence: 99%

A toolset to study functions of Cytosolic non-specific dipeptidase 2 (CNDP2) using Drosophila as a model organism

et al. 2019

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BackgroundExpression of the CNDP2 gene is frequently up- or down-regulated in different types of human cancers. However, how the product of this gene is involved in cell growth and proliferation is poorly understood. Moreover, our knowledge of the functions of the CNDP2 orthologs in well-established model organisms is scarce. In particular, the function of the D. melanogaster ortholog of CNDP2, encoded by the CG17337 gene (hereafter referred to as dCNDP2), is still unknown.ResultsThis study was aimed at developing a set of genetic and molecular tools to study the roles of dCNDP2. We generated a dCNDP2 null mutation (hereafter ∆dCNDP2) using CRISPR/Cas9-mediated homologous recombination (HR) and found that the ∆dCNDP2 mutants are homozygous viable, morphologically normal and fertile. We also generated transgenic fly lines expressing eGFP-tagged and non-tagged dCNDP2 protein, all under the control of the UAS promoter, as well as polyclonal antibodies specific to dCNDP2. Using these tools, we demonstrate that only one of the two predicted dCNDP2 isoforms is expressed throughout the different tissues tested. dCNDP2 was detected in both the cytoplasm and the nucleus, and was found to be associated with multiple sites in the salivary gland polytene chromosomes.ConclusionsThe dCNDP2 gene is not essential for fly viability under standard laboratory conditions. The subcellular localization pattern of dCNDP2 suggests that this protein might have roles in both the cytoplasm and the nucleus. The genetic and molecular tools developed in this study will allow further functional characterization of the conserved CNDP2 protein using D. melanogaster as a model system.Electronic supplementary materialThe online version of this article (10.1186/s12863-019-0726-z) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A toolset to study functions of Cytosolic non-specific dipeptidase 2 (CNDP2) using Drosophila as a model organism

et al. 2019

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“…According to bioinformatics prediction, our knowledge, Co-IP and double staining, we found that PGC bound to CCNT1, CNDP2 and CTSB. Reportedly, CCNT1 is related to T lymphocyte differentiation and malignant transformation by interacting with CDK9 [ 20 ]; CNDP2 is a nonspecific metallopeptidase for the hydrolysis of carnosine and several other dipeptides [ 21 ]; CTSB is a lysosomal cysteine endopeptidase and associated with metastasis of cancer cells [ 22 ]. Therefore, we speculated that the partner proteins of PGC might be involved in the regulation of aggressiveness of gastric cancer cells, such as proliferation and metastasis.…”

Section: Discussionmentioning

confidence: 99%

The relationship between pepsinogen C and gastric carcinogenesis: a transgene and population study

Ying

Sun

et al. 2023

BMC Cancer

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Background Pepsinogen C (PGC) is expressed in chief cells, fundic mucous neck cells, and pyloric gland cells of gastric epithelium and also in breast, prostate, lung, and seminal vesicles. Methods We explored the clinicopathological and prognostic significances of PGC mRNA using pathological and bioinformatics analyses. We generated PGC knockout and PGC-cre transgenic mice to observe the effects of PGC deletion and PTEN abrogation in PGC-positive cells on gastric carcinogenesis. Finally, we observed the effects of altered PGC expression on aggressive phenotypes by CCK8, Annexin V staining, wound healing and transwell assays and analyzed the partner proteins of PGC using co-IP (co-immunoprecipitation) and double fluorescence staining. Results PGC mRNA level was inversely correlated with the T and G stage and a short survival of gastric cancer (p < 0.05). PGC protein expression was negatively linked to lymph node metastasis, dedifferentiation, and low Her-2 expression of gastric cancer (p < 0.05). No difference in body weight or length was evident between wild-type (WT) and PGC knockout (KO) mice (p > 0.05), but PGC KO mice had a shorter survival than WT mice (p < 0.05). No gastric lesions were observed in the mucosa of the granular stomach in PGC KO mice, which displayed lower frequency and severity of gastric lesion than in WT mice after treated with MNU. Transgenic PGC-cre mice showed high cre expression and activity in the lung, stomach, kidney, and breast. Gastric cancer and triple-negative lobular breast adenocarcinoma were found in PGC-cre/PTENf/f mice with two previous pregnancies and breast feeding, but breast cancer was not seen in transgenic mice exposed to either estrogen or progesterone, or those with two previous pregnancies and no breast feeding. PGC suppressed proliferation, migration, invasion, and induced apoptosis, and interacted with CCNT1, CNDP2 and CTSB. Conclusion PGC downregulation was seen in gastric cancer, but PGC deletion resulted in resistance to chemically-induced gastric carcinogenesis. PGC expression suppressed the proliferation and invasion of gastric cancer cells possibly by interacting with CCNT1, CNDP2 and CTSB. Spontaneous triple-negative lobular adenocarcinoma and gastric cancer were seen in PGC-cre/PTENf/f mice, and the breast carcinogenesis was closely linked to pregnancy and breast feeding, but not to single exposure to estrogen or progesterone, or pregnancy. Limiting either pregnancy or breast feeding might help to prevent hereditary breast cancer.

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“…Tissue carnosine dipeptidase 2 (CN2) is the only known enzyme capable of degrading carnosine in skeletal muscle. However, CN2 is nonspecific and has a low affinity for carnosine (38). Moreover, the literature is controversial as to whether CN2 has catalytic activity toward carnosine under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Muscle Carnosine Decay after β-Alanine Supplementation: A 16-wk Washout Study

Yamaguchi¹,

Nemezio²,

Schulz

et al. 2020

Medicine &Amp; Science in Sports &Amp; Exercise

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The zinc form of carnosine dipeptidase 2 (CN2) has dipeptidase activity but its substrate specificity is different from that of the manganese form

Cited by 6 publications

References 26 publications

A toolset to study functions of Cytosolic non-specific dipeptidase 2 (CNDP2) using Drosophila as a model organism

A toolset to study functions of Cytosolic non-specific dipeptidase 2 (CNDP2) using Drosophila as a model organism

The relationship between pepsinogen C and gastric carcinogenesis: a transgene and population study

Kinetics of Muscle Carnosine Decay after β-Alanine Supplementation: A 16-wk Washout Study

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