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Single amino-acid substitution in the N-terminal arm altered the tetramer stability of rat muscle lactate dehydrogenase a

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Science China(Life Sciences) 2001年第6期44卷 576-584页

作者：袁翀胡红雨许根俊 Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China

lactate dehydrogenase a (LDHA) is a well-characterized tetrameric enzyme. Its N-terminal arm, comprised of an α-helix and a p-strand, was suggested to be essential for subunit interactions. To examine the critical amino acid residues in the N-terminus involved in the subunit association, two single-point mutants, Leu3Pro (L3P) and IIe8GIu (I8E), have been constructed. We compared the stability of WT-LDHA (WT) and its variants by unfolding experiments. For WT, a dimeric but inactive intermediate was observed by size-exclusion chromatography at 0.6-0.8 mol/L GdmCI. Leu3Pro exists in an active tetrameric structure in aqueous solution as WT does, but it dissociates into dimers under lower concentration of GdmCI (0.2 mol/L). In aqueous solution, the lle8GIu variant exists predominantly in the dimeric form with increased KM and decreased kcat as compared with those of WT and L3P. However, the activity of lle8GIu increases significantly in the presence of sodium sulfate. In conclusion, two mutants are less stable than WT in oligomer structure. Results also support the fact that some residues in the N-terminal arm, especially the Leu8 in the p-structure, contribute the important binding energies to the dimerization of dimers, which might affect the assembly of the enzyme as well as the catalytic function.

关键词： lactate dehydrogenase a N-terminal residues size-exclusion chromatograph tetramer stability site-directed mutagenesis unfolding experiments subunit interaction.

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Lysine acetylation decreases enzyme activity and protein level of Escherichia coli lactate dehydrogenase

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Engineering Microbiology 2022年第4期2卷 1-7页

作者： Min Liu Meitong Huo Likun Guo Yingxin Fu Mo Xian Qingsheng Qi Wei Liu Guang Zhao State Key Laboratory of Microbial Technology Shandong UniversityQingdao 266237China Institute of Corrosion Science and Technology Guangzhou 510530China CAS Key Laboratory of Biobased Materials Qingdao Institute of Bioenergy and Bioprocess TechnologyChinese Academy of SciencesQingdao 266101China

lactate is an important bulk chemical with widespread applications and a major byproduct of other chemicals bioprocess in microbial *** dehydrogenase A(LdhA)catalyzes the synthesis of lactate from *** acetylation is an evolutionarily conserved post-translational modification;however,the mech-anisms underlying the regulation of LdhA function by lysine acetylation in Escherichia coli remain poorly ***,we demonstrate acetylation of *** LdhA occurs via enzymatic and non-enzymatic ***,we show carbon source type and concentration affect the lysine acetylation status of LdhA via a non-enzymatic *** acetylation significantly inhibits the enzymatic activity and protein level of *** results of the present study demonstrate lysine acetylation of *** LdhA is *** of the effects of lysine acetylation on LdhA function may provide a new perspective for regulating lactate production in microbial synthesis.

关键词： Lysine acetylation lactate dehydrogenase a lactate synthesis Protein degradation

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Lipid nanoparticle-mediated CRISPR/Cas9 gene editing and metabolic engineering for anticancer immunotherapy

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Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 641-652页

作者： Hyemin Ju Dongyoon Kim Yu-Kyoung Oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul 08826Republic of Korea

Metabolic engineering of the tumor microenvironment has emerged as a new *** dehydrogenase A(LDHA)is a prominent target for metabolic ***,we designed a cationic lipid nanoparticle formulation for LDHA gene *** plasmid DNA delivery efficiency of our lipid nanoparticle formulations was screened by testing the fluorescence of lipid nanoparticles complexed to plasmid DNA encoding green fluorescence protein(GFP).The delivery efficiency was affected by the ratios of three components:a cationic lipid,cholesterol or its derivative,and a fusogenic *** lipid nanoparticle designated formulation F3 was complexed to plasmid DNA co-encoding CRISPR-associated protein 9 and LDHA-specific sgRNA,yielding the lipoplex,pCas9-sgLDHA/*** lipoplex including GFP-encoding plasmid DNA provided gene editing in HeLa-GFP *** of B16F10 tumor cells with pCas9-sgLDHA/F3 yielded editing of the LDHA gene and increased the pH of the culture ***9-sgLDHA/F3 treatment activated the interferon-gamma and granzyme production of T cells in *** vivo,combining pCas9-sgLDHA/F3 with immune checkpoint-inhibiting anti-PD-L1 antibody provided a synergistic antitumor effect and prolonged the survival of tumor model *** study suggests that combining metabolic engineering of the tumor microenvironment with immune checkpoint inhibition could be a valuable antitumor strategy.

关键词： Gene editing Lipid nanoparticle Metabolic engineering lactate dehydrogenase a Tumor microenvironment

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LDHA Desuccinylase Sirtuin 5 as A Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer

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Genomics, Proteomics & Bioinformatics 2023年第1期21卷 177-189页

作者： Oh Kwang Kwon In Hyuk Bang So Young Choi Ju Mi Jeon Ann-Yae Na Yan Gao Sam Seok Cho Sung Hwan Ki Youngshik Choe Jun Nyung Lee Yun-Sok Ha Eun Ju Bae Tae Gyun Kwon Byung-Hyun Park Sangkyu Lee BK21 Plus KNU Multi-Omics Based Creative Drug Research Team College of PharmacyResearch Institute of Pharmaceutical SciencesKyungpook National UniversityDaegu 41566Republic of Korea Department of Biochemistry and Molecular Biology Chonbuk National University Medical SchoolJeonjuJeonbuk 54896Republic of Korea College of Pharmacy Chosun UniversityGwangju 61452Republic of Korea Korea Brain Research Institute Daegu 41068Republic of Korea Department of Urology School of MedicineKyungpook National UniversityDaegu 41566Republic of Korea Department of Urology Kyungpook National University HospitalDaegu 41566Republic of Korea College of Pharmacy Chonbuk UniversityJeonjuJeonbuk 54896Republic of Korea School of Pharmacy Sungkyunkwan UniversitySuwon 16419Republic of Korea

Prostate cancer(PCa)is the most commonly diagnosed genital cancer in men *** 80%of the patients who developed advanced PCa suffered from bone metastasis,with a sharp drop in the survival *** great efforts,the detailed mechanisms underlying castration-resistant PCa(CRPC)remain *** 5(SIRT5),an NAD+-dependent desuccinylase,is hypothesized to be a key regulator of various ***,compared to other SIRTs,the role of SIRT5 in cancer has not been extensively ***,we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa *** correlation between the decrease in the SIRT5 level and the patient’s reduced survival rate was also *** quantitative global succinylome analysis,we characterized a significant increase in the succinylation at lysine 118(K118su)of lactate dehydrogenase a(LDHA),which plays a role in increasing LDH *** a substrate of SIRT5,LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa *** study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression,which could serve as a new target to prevent CPRC progression for PCa treatment.

关键词： Sirtuin 5 lactate dehydrogenase a Lysine succinylation PCa progression

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Regulatory effects of evodiamine on glucose metabolism-related factors in CT26 colorectal carcinoma-bearing mice

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Precision Medicine Research 2022年第4期4卷 12-17页

作者： Jiang-Yue Yu Kui Chen Ruo-Qin Zhao Li-Qun Wang Chao Gong Shen-Zhou Huang Yun-Juan Zheng Pei-Wen Zhu Xin-Ran Song Fang-Hua Wu General Surgery Fujian Medical University Affiliated Fuzhou First HospitalFuzhou 350009China College of Forestry Shanxi Agricultural UniversityJinzhong 030801China School of Bioengineering Tianjin Modern Vocational Technology CollegeTianjin 300350China

Objective:To investigate the therapeutic effect of evodiamine(EVO)on the expression of hexokinase(HK),lactate dehydrogenase a(LDHA),and pyruvate kinase M(PKM),key enzymes of glycolysis,in the tumor-bearing mice after modeling mouse colon cancer cells(CT26).Methods:A tumor-bearing mouse model was generated by administering axillary injection of CT26 and intraperitoneally injecting different doses of *** therapeutic effects of EVO on CT26 tumor-bearing mice were evaluated by measuring the thymus and spleen indices,tumor volume,tumor suppression rate,and other related indicators in the tumor tissues of mice in each group after the administration of EVO,in addition,histopathological changes in the tumor tissues of the mice in the groups were studied by hematoxylin and eosin *** expression levels of HK,LDHA,and PKM in the tumor tissues of each group of mice were measured by performing Western blot to investigate the mechanism of EVO treatment in CT26 tumor-bearing ***:EVO inhibited the growth of tumors in CT26-bearing mice and enhanced their splenic and thymic *** blot results showed that EVO reduced the expression levels of HK,LDHA,and PKM proteins in the tumor tissues of CT26 tumor-bearing ***:EVO has a therapeutic effect on CT26 tumor-bearing mice,and its mechanism of action may be related to the low expression of key enzymes HK,LDHA and PKM of glycolysis in tumor tissues.

关键词： evodiamine mouse colon cancer cells tumor-bearing mice glycolysis hexokinase lactate dehydrogenase a pyruvate kinase M

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