ACS Sustainable Chemistry & Engineering
·
2021
·
IF 8.198
Hai-Peng Li,Zhi-Neng You,Yuan-Yang Liu,Gao-Wei Zheng,Heng Gong,Yiming Mo,Ning Zhu,Yun-Peng Bai,Jian-He Xu
Water-forming NAD(P)H oxidases (NOXs) constitute a clean NAD(P)+ regeneration strategy for NAD(P)+-dependent biotransformations to produce high value-added chemicals because they only consume oxygen and generate water. However, the application of NOXs is still challenging because of limited oxygen transfer in batch reactions. Here, we report an efficient continuous-flow microreactor (CFMR) to improve the oxygen transfer and reaction performance in NAD+-dependent chenodeoxycholic acid oxidation catalyzed by 7α-hydroxysteroid dehydrogenase (7α-HSDH) for the production of 7-oxo-lithocholic acid, a key precursor of ursodeoxycholic acid. The recycling efficiency of NAD+ by NOX from Streptococcus mutans (SmNOX) was significantly improved in this CFMR. Compared with a conventional batch stirred tank reactor, the space–time yield of production of 7-oxo-lithocholic acid was increased by 96-fold. Furthermore, the total turnover number of NAD+ was improved 10-fold, and the enzyme consumption number was decreased 7-fold. Combining the NOX/O2 system with this microreactor technology provides a general platform that enables various NAD(P)+-dependent biotransformations in a green and sustainable manner, which will be helpful in the design of ecofriendly bioprocesses for production of functional chemicals on a large scale.
研究领域:
生物化学
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合成生物学
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绿色化学
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DOI
高影响因子
REDOX REPORT
·
2025
·
IF 7.4
Fang Cheng,Minzhu Zhao,Qi Wang,Hongli Xiong,Kai Yu,Chong Chen,Ying Zhu,Yemiao Chen,Jianbo Li
Objectives Doxorubicin (DOX) induces dose-dependent cardiotoxicity, primarily through oxidative stress and metabolic dysregulation. Although NAD+ deficiency has been implicated in cardiovascular pathology, its role in DOX-induced cardiotoxicity (DIC) remains poorly understood. This study investigated NAD+ metabolism dysregulation as a redox-sensitive mechanism in DIC pathogenesis.Methods Human cardiomyocytes (AC16), mouse atrial myocytes (HL-1), and C57BL/6 mice were used to establish the DIC model. The role and mechanism of NAD+ in DIC were investigated using a range of methods.Results Using integrated in vitro and in vivo models, we demonstrated that DOX induces myocardial oxidative damage accompanied by NAD+ depletion. Exogenous NAD+ supplementation mitigated the DOX-induced cardiomyocyte death and redox imbalance. Mechanistically, pharmacological CD38 inhibition with 78C or genetic silencing failed to restore the NAD+ pool, whereas nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) overexpression, combined with nicotinamide mononucleotide (NMN) administration, effectively rescued NAD+ levels and attenuated oxidative stress. Computational and functional analyses identified FOXO1 as a transcriptional repressor of NMNAT3 following DOX exposure.Conclusion This study establishes the dysregulation of the FOXO1-NMNAT3 axis as a key mechanism underlying NAD+ depletion in DIC. Targeting this axis through NAD+ replenishment, particularly by activating NMNAT3, offers a novel redox-based therapeutic strategy against DIC.
研究领域:
心血管病理学
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分子生物学
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药理学
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氧化应激
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代谢调控
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转化医学
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药物毒性
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Xinyi Lu,Pingping Jin,Qianyun Tang,Min Zhou,Hanjie Xu,Chen Su,Lei Wang,Feng Xu,Min Zhao,Yongxiang Yin,Jinqiu Zhang,Zhen Jia,Xinrui Peng,Jie Zhou,Lu Wang,Yan Chen,Min Wang,Min Yang,Daozhen Chen,Yu Chen
Cervical cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD-1/PD-L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD + ) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD-L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD-L1 overexpression in cancers is regulated by both transcriptional and post-transcriptional processes. Acetyl-proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD-L1 subcellular distribution. This finding reveals the epigenetic control of immune checkpoint proteins by metabolic pathways, offering a new perspective on the regulation of PD-L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.
研究领域:
肿瘤学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING SCIENCE
·
2019
·
IF 3.372
Huan Xia,Zhixian Li,Xue Zhong,Binghui Li,Yunpeng Jiang,Yanbin Jiang
The combination of enzymatic and chemical reactions to achieve co-operative chemo-enzymatic processes has presented many challenges for decades. In this work, alcohol dehydrogenase (ADH) was encapsulated into metal-organic framework HKUST-1 crystals through an in situ approach to construct a synergistic chemo- and bio-catalysis system, where ADH was for the conversion of benzyl alcohol to benzaldehyde, and HKUST-1 was in charge for the regeneration of β-nicotinamide adenine dinucleotide (NAD + , the oxidized cofactor). It was found that HKUST-1 was a versatile catalyst for efficient oxidation of NADH in different buffers. The Michaelis-Menten kinetic parameters of immobilized ADH exhibited an increased K M (approximately 1.3-fold) and a decreased V max (approximately 4.7-fold) compared to free ADH. Due to the protection of HKUST-1, the immobilized enzyme showed a better resistance against urea and organic solvents compared with free enzyme, and still maintained 93% of its original activity after 6 cycles. The immobilized enzyme was successfully applied to the enzymatic transformation of benzyl alcohol to benzaldehyde in aqueous media at room temperature. Owing to the oxidized cofactor regeneration by HKUST-1, ADH@HKUST-1 composites achieved a benzaldehyde yield of 28.5%, which was approximately 4.3-fold higher than that of the individual bio-catalysis. This concept of combining chemo- and bio-catalysis may provide a novel and versatile technique for applications in biochemical catalysis, biosensors and drug delivery.
研究领域:
生物化学
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催化科学
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DOI
高影响因子
VIEW
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2025
·
IF 8.5
Youjia Zhang,Ming Chen,Yi Tian,Bo Qin,Xiaoxiao Chen,Yiwen Zhou,Jinhai Huang,Mei Yang,Xinghuai Sun,Yuan Lei,Yuhong Chen
Elevated intraocular pressure (IOP) is a critical risk factor for the development and progression of glaucoma. However, current treatments focus primarily on mechanical stress relief, neglecting the underlying issue of diminished cellular energy production in patients. In this study, we investigated the impact of NAD + reduction on IOP regulation and explored the potential of NAD + precursors as a therapeutic strategy. We investigated the role of NAD + metabolism in glaucoma and revealed decreased nicotinamide phosphoribosyltransferase (NAMPT) expression in both patients and the human trabecular meshwork (HTM) cell model. Supplementation with NAD + precursors, nicotinamide (NAM) or nicotinamide mononucleotide (NMN), provided protective effects in H 2 O 2 -treated HTM cells and reduced IOP in ocular hypertension mouse models by mitigating senescence, extracellular matrix accumulation, and oxidative stress. To optimize drug delivery, we engineered the NAM@CeMOF-2 nanozyme system, which achieved a maximum IOP reduction in Cav1 ⁻/⁻ mice following 7 days of treatment. This localized treatment improved bioavailability and reduced systemic side effects. These findings suggest that NAD + deficiency plays a role in glaucoma development and propose novel therapeutic targets for addressing cellular dysfunction in glaucoma.
研究领域:
医学
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生物化学
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眼科研究
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DOI
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-13
·
IF 14.7
Hong Yechun,Yu Zongjun,Zhou Qian,Chen Chunyu,Hao Yuqiong,Wang Zhen,Zhu Jian-Kang,Guo Hongwei,Huang Ancheng C.
Nicotinamide adenine dinucleotide (NAD + ) is a redox cofactor and signal central to cell metabolisms. Disrupting NAD homeostasis in plant alters growth and stress resistance, yet the underlying mechanisms remain largely unknown. Here, by combining genetics with multi-omics, we discover that NAD + deficiency in qs-2 caused by mutation in NAD + biosynthesis gene- Quinolinate Synthase retards growth but induces biosynthesis of defense compounds, notably aliphatic glucosinolates that confer insect resistance. The elevated defense in qs-2 is resulted from activated jasmonate biosynthesis, critically hydroperoxidation of α-linolenic acid by the 13-lipoxygenase (namely LOX2), which is escalated via the burst of chloroplastic ROS-singlet oxygen ( 1 O 2 ). The NAD + deficiency-mediated JA induction and defense priming sequence in plants is recapitulated upon insect infestation, suggesting such defense mechanism operates in plant stress response. Hence, NAD homeostasis is a pivotal metabolic checkpoint that may be manipulated to navigate plant growth and defense metabolism for stress acclimation.
研究领域:
植物学
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遗传学
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代谢组学
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DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
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2013
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IF 5.056
Yadong Hu,Helin Wang,Qingtao Wang,Haiteng Deng
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells and mediates multiple cellular signaling pathways. In the present study, a 35% decrease of cellular NAD level is achieved by stable expression of the N-terminal truncated CD38, a NAD hydrolase. CD38-expressing (CD38(+)) cells have the lower growth rate and are more susceptive to oxidative stress than the wild type cells and empty vector-transfected (CD38(−)) cells. Quantitative proteomic analysis shows that 178 proteins are down-regulated in CD38(+) cells, which involve in diverse cellular processes including glycolysis, RNA processing and protein synthesis, antioxidant, and DNA repair. Down regulation of six selected proteins is confirmed by Western blotting. However, down-regulation of mRNA expressions of genes associated with glycolysis, antioxidant, and DNA repair is less significant than the corresponding change in protein expression, suggesting the low NAD level impairs the protein translational machinery in CD38(+) cells. Down-regulation of antioxidant protein and DNA-repair protein expression contributes to the susceptibility of CD38(+) cells to oxidative stress. Taken together, these results demonstrate that CD38(+) cells are a useful model to study effects of the cellular NAD levels on cellular processes and establish a new linker between cellular NAD levels and oxidative stress.
研究领域:
分子生物学
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
TRENDS IN BIOTECHNOLOGY
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2025
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IF 14.9
Panpan Wu,Zhenyue Xu,Zhongqiu Meng,Ketao Chen,Hao Lin,Min Zhang,Lixin Zhang,Buchang Zhang,Hang Wu
Nicotinamide adenine dinucleotide (NAD) homeostasis is crucial for secondary metabolism in antibiotic-producing actinomycetes. However, NAD-based dynamic control strategies for boosting antibiotic titers have not been reported. We identified SACE_1905, an alcohol dehydrogenase in Saccharopolyspora erythraea , which converts NADH to NAD + . Overexpressing SACE_1905 lowered the cellular NADH/NAD + ratio, facilitating carbon source utilization and erythromycin biosynthetic precursor supply, concurrently improving cell growth and erythromycin yield. To balance primary and secondary metabolism, we developed a strategy that fine-tunes SACE_1905 expression with inducible clustered regularly interspaced short palindromic repeat interference (CRISPRi) to dynamically modulate the NADH/NAD + ratio, which we named diNAD. Optimized diNAD redirected carbon flux, maximizing erythromycin biosynthesis at a moderate NADH/NAD + ratio during the stationary phase. Based on its utility in actinorhodin and avermectin overproduction in Streptomyces coelicolor and Streptomyces avermitilis , we show that diNAD is effective in augmenting antibiotic titers in actinomycetes.
研究领域:
微生物学
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生物技术
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合成生物学
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生物工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nature Cardiovascular Research
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2025
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IF 10.8
Zhang Jingjing,Tang Yuyi,Zhang Shan,Xie Zhuxin,Ma Wenrui,Liu Shaowen,Fang Yixuan,Zheng Shufen,Huang Ce,Yan Guoquan,Abudupataer Mieradilijiang,Xin Yue,Zhu Jingqiao,Han Wenjing,Wang Weizhong,Shen Fenglin,Lai Hao,Liu Yang,Ye Dan,Yu Fa-Xing,Xu Yanhui,Pan Cuiping,Wang Chunsheng,Zhu Kai,Zhang Weijia
Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD + salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD + transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt , Nmnat1 , Nmnat3 , Slc25a51 , Nadk2 and Aldh18a1 , genes involved in NAD + salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.
研究领域:
心血管疾病
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分子生物学
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遗传学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
ACS Catalysis
·
2024
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IF 11.3
Zaixiang Xu,Fengcang Zhou,Hanchi Chen,Jianguo Wang
The regeneration of NAD(P)H and its analogues is crucial for biocatalytic processes. However, despite the efficiency of enzymatic catalysis in regenerating NAD(P)H, the sustainability of enzymes is often compromised, particularly under extreme catalytic conditions. Moreover, artificial cofactors may present advantages in certain reactions due to their stability and versatility, yet the substrate specificity of enzymes poses significant challenges to their regeneration through the enzymatic method. Therefore, it is imperative to develop a highly stable regeneration method that can be adapted to both natural and artificial cofactors. In this work, employing potassium-ion-doped carbon nitride (ionCN-0.2) as a catalyst not only achieves high-efficiency photocatalytic regeneration of NAD(P)H, comparable to that of glucose dehydrogenase (GDH), but also a remarkable ability to regenerate nicotinamide analogues. This enhanced performance stems from the tunable negative ζ-potential, which effectively adsorbs the positively charged [Cp*Rh(bpy)H2O]2+ mediator, resulting in enhanced regeneration kinetics of the nicotinamide moiety. The catalyst demonstrates superior performance compared to the reported systems; the optimal regeneration rate reaches 0.55 mmol L–1 gcat–1 min–1 and approaches enzymatic regeneration efficiency. Expanding the reaction conditions to a wider temperature and pH range also confirms the effectiveness and sufficient stability of this photocatalytic system, offering a promising strategy for stable cofactor regeneration in biocatalytic processes.
研究领域:
生物化学
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材料科学
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催化化学
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产品关联
DOI
高影响因子
BIOPROCESS AND BIOSYSTEMS ENGINEERING
·
2016
·Vol. 39
·期 4
·603-611
·
IF 1.901
Zhang Jian-Dong,Cui Zhi-Mei,Fan Xiao-Jun,Wu Hua-Lei,Chang Hong-Hong
Two uncharacterized nicotinamide adenine dinucleotide (NADH) oxidases (named as LpNox1, LpNox2) from Lactobacillus pentosus ATCC 8041 were cloned and overexpressed in Escherichia coli BL21 (DE3). The sequence analysis revealed that the two enzymes are water-forming Noxs with 64 % and 52 % identity to LbNox from Lactobacillus brevis DSM 20054. The optimal pH and temperature of the purified LpNox1 and LpNox2 were 7.0 and 8.0 and 35 and 40 °C, respectively, with K
M of 99.0 μM (LpNox1) and 27.6 μM (LpNox2), and yielding catalytic efficiency k
cat / K
M of 1.0 and 0.2 μM −1 s −1 , respectively. Heat inactivation studies revealed that the two enzymes are relatively instable. The application of LpNox1 for the regeneration of NAD + was demonstrated by coupling with a glycerol dehydrogenase-catalyzed oxidation of glycerol to 1,3-dihydroxyacetone. The characteristics of the LpNox1 could prove to be of interest in industrial application such as NAD + regeneration in dehydrogenase-catalyzed oxidations.
研究领域:
生物化学
·
微生物学
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DOI
PubMed
高影响因子
Science China-Life Sciences
·
2025
·
IF 9.5
Gui Tianxiang,Liu Ying,Fu Mingfeng,Wu Han,Su Pan,Feng Xuhui,Zheng Mengmeng,Huang Zixuan,Luo Xudong,Boron Walter F.,Chen Li-Ming
Nicotinamide adenine dinucleotide (NAD) is well known as a coenzyme involved in many redox reactions in cellular energy metabolism, or as a substrate for many NAD + -consuming enzymes, including those that generate the second messenger cyclic ADP-ribose or deacetylate proteins (e.g., histones). The role of NAD in non-catalytic proteins is poorly understood. IRBIT and L-IRBIT (the IRBITs) are two cytosolic proteins that are structurally related to dehydrogenases but lack catalytic activity. Instead, by interacting directly with their targets, the IRBITs modulate the function of numerous proteins with important roles, ranging from Ca 2+ signaling and intracellular pH (pH i ) regulation to DNA metabolism to autophagy. Among the targets of the IRBITs is the Na + -HCO 3 − cotransporter NBCe1-B, which plays a central role in intracellular pH (pH i ) regulation and epithelial electrolyte transport. Here, we demonstrate that NAD modulates NBCe1-B activation by serving as a cofactor of IRBIT or L-IRBIT. Blocking NAD salvage pathway greatly decreases NBCe1-B activation by the IRBITs. Administration of the oxidized form NAD + enhances, whereas the reduced form NADH decreases NBCe1-B activity. Our study represents the first example in which the redox state of NAD, via IRBIT or L-IRBIT, modulates the function of a membrane transport protein. Our findings reveal a new role of NAD and greatly expand our understanding of NAD biology. Because the NAD redox state fluctuates greatly with metabolic status, our work provides insight into how, via the IRBITs, energy metabolism could affect pH i regulation and many other IRBIT-dependent processes.
研究领域:
生物化学
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细胞生物学
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生理学
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DOI
PubMed
高影响因子
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