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Linkage of nanosecond protein motion with enzymatic methyl transfer by nicotinamide N-methyltransferase.

ABSTRACT: Nicotinamide N-methyltransferase (NNMT), a key cytoplasmic protein in the human body, is accountable to catalyze the nicotinamide (NCA) N¹-methylation through S-adenosyl-L-methionine (SAM) as a methyl donor, which has been linked to many diseases. Although extensive studies have concerned about the biological aspect, the detailed mechanism study of the enzyme function, especially in the part of protein dynamics is lacking. Here, wild-type nicotinamide N-methyltransferase together with the mutation at position 20 with Y20F, Y20G, and free tryptophan were carried out to explore the connection between protein dynamics and catalysis using time-resolved fluorescence lifetimes. The results show that wild-type nicotinamide N-methyltransferase prefers to adapt a less flexible protein conformation to achieve enzyme catalysis.

SUBMITTER: Jing Y

PROVIDER: S-EPMC8313939 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Linkage of nanosecond protein motion with enzymatic methyl transfer by nicotinamide N-methyltransferase.

Jing Yahui Y Cheng Yiting Y Li Fangya F Li Yuping Y Liu Fan F Zhang Jianyu J

Turkish journal of biology = Turk biyoloji dergisi 20210623 3

Nicotinamide N-methyltransferase (NNMT), a key cytoplasmic protein in the human body, is accountable to catalyze the nicotinamide (NCA) N<sup>1</sup>-methylation through S-adenosyl-L-methionine (SAM) as a methyl donor, which has been linked to many diseases. Although extensive studies have concerned about the biological aspect, the detailed mechanism study of the enzyme function, especially in the part of protein dynamics is lacking. Here, wild-type nicotinamide N-methyltransferase together with ...[more]

PMID: 34377057

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Project description:BackgroundNicotinamide N-methyltransferase (NNMT) is overexpressed in various human tumors and involved in the development and progression of several carcinomas. In breast cancer, NNMT was found to be overexpressed in several cell lines. However, the clinical relevance of NNMT in breast cancer is not yet clear.MethodsNNMT expression in breast carcinoma was examined by immunohistochemistry, and then, its relationship with patient clinicopathological characteristics was analyzed. The effects of NNMT on chemoresistance in breast cancer cells were assessed by cell viability, colony formation, and apoptosis assay. The NNMT, SIRT1, p53, and acetyl-p53 proteins, which are involved in NNMT-related chemoresistance, were examined by Western blotting. The SIRT1 mRNA was examined by real-time PCR, and its activity was measured by using the SIRT1 deacetylase fluorometric reagent kit.ResultsNNMT expression was significantly higher (53.9%) in breast carcinoma than in paracancerous tissues (10.0%) and breast hyperplasia (13.3%). A high level of NNMT expression correlated with poor survival and chemotherapy response in breast cancer patients who received chemotherapy. Ectopic overexpression of NNMT significantly inhibited the apoptotic cell death and suppression of colony formation induced by adriamycin and paclitaxel. Mechanistic studies revealed that NNMT overexpression increased SIRT1 expression and promoted its activity. Either inhibition of SIRT1 by EX527 or knockdown of SIRT1 by siRNA could reverse NNMT-mediated resistance to adriamycin and paclitaxel, which suggests that SIRT1 plays a critical role in NNMT-related chemoresistance in breast cancer.ConclusionsThe results of this study demonstrate a novel correlation between the NNMT expression level and patient survival, suggesting that NNMT has the potential to become a new prognostic biomarker to predict the treatment outcomes of the clinical chemotherapy in breast cancer. Moreover, targeting NNMT or downstream SIRT1 may represent a new therapeutic approach to improve the efficacy of breast cancer chemotherapy.

Dataset Information

Linkage of nanosecond protein motion with enzymatic methyl transfer by nicotinamide N-methyltransferase.

Publications

Linkage of nanosecond protein motion with enzymatic methyl transfer by nicotinamide N-methyltransferase.

Similar Datasets

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