207 results match your criteria pdhc activity

Discovery of efficient inhibitors against pyruvate dehydrogenase complex component E1 with bactericidal activity using computer aided design.

Pestic Biochem Physiol 2021 Aug 9;177:104894. Epub 2021 Jun 9.

Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China. Electronic address:

Computer aided optimization of lead compounds is of great significance to the design and discovery of new agrochemicals. A series of 2,6-dimethyl-4-aminopyrimidine acylhydrazones 6 was rationally designed as pyruvate dehydrogenase complex component E1 (PDHc-E1) inhibitors using computer aided drug design. Compounds in series 6 showed excellent inhibitory activity against Escherichia coli PDHc-E1, which was considerably higher than that of the lead compound A2. Read More

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[Research of progress of pyruvate dehydrogenase complex in sepsis metabolism].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2021 Jun;33(6):765-768

Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, China.

Sepsis is a critical illness with high morbidity and mortality. Anaerobic glycolysis plays an important role in the pathogenesis of sepsis. Pyruvate dehydrogenase complex (PDHC) serves as a key regulator during sepsis. Read More

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Pyruvate dehydrogenase deficiency disease detected by the enzyme activity of peripheral leukocytes.

Mol Genet Genomic Med 2021 Jun 22:e1728. Epub 2021 Jun 22.

ChinovoLaboratory, Beijing, P. R. China.

Background: Pyruvate dehydrogenase complex (PDHC) deficiency is a common neurodegenerative disease associated with abnormal mitochondrial energy metabolism. The diagnosis of PDHC is difficult because of the lack of a rapid, accurate, and cost-effective clinical diagnostic method.

Methods: A 4-year-old boy was preliminarily diagnosed with putative Leigh syndrome based on the clinical presentation. Read More

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Design, Synthesis, and Antifungal Activity of 2,6-Dimethyl-4-aminopyrimidine Hydrazones as PDHc-E1 Inhibitors with a Novel Binding Mode.

J Agric Food Chem 2021 Jun 19;69(21):5804-5817. Epub 2021 May 19.

Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, P. R. China.

A series of novel 2,6-dimethyl-4-aminopyrimidine hydrazones were rationally designed and synthesized as pyruvate dehydrogenase complex E1 (PDHc-E1) inhibitors. Compounds strongly inhibited () PDHc-E1 (IC values 0.94-15. Read More

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Integrative structure of a 10-megadalton eukaryotic pyruvate dehydrogenase complex from native cell extracts.

Cell Rep 2021 Feb;34(6):108727

Interdisciplinary Research Center HALOmem, Charles Tanford Protein Center, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Straße 3a, Halle/Saale, Germany; Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Straße 3, Halle/Saale, Germany; Biozentrum, Martin Luther University Halle-Wittenberg, Weinbergweg 22, Halle/Saale, Germany. Electronic address:

The pyruvate dehydrogenase complex (PDHc) is a giant enzymatic assembly involved in pyruvate oxidation. PDHc components have been characterized in isolation, but the complex's quaternary structure has remained elusive due to sheer size, heterogeneity, and plasticity. Here, we identify fully assembled Chaetomium thermophilum α-keto acid dehydrogenase complexes in native cell extracts and characterize their domain arrangements utilizing mass spectrometry, activity assays, crosslinking, electron microscopy (EM), and computational modeling. Read More

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February 2021

Metabolic Detoxification of 2-Oxobutyrate by Remodeling Acetate Bypass.

Metabolites 2021 Jan 4;11(1). Epub 2021 Jan 4.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China.

2-Oxobutyrate (2-OBA), as a toxic metabolic intermediate, generally arrests the cell growth of most microorganisms and blocks the biosynthesis of target metabolites. In this study, we demonstrated that using the acetate bypass to replace the pyruvate dehydrogenase complex (PDHc) in could recharge the intracellular acetyl-CoA pool to alleviate the metabolic toxicity of 2-OBA. Furthermore, based on the crystal structure of pyruvate oxidase (PoxB), two candidate residues in the substrate-binding pocket of PoxB were predicted by computational simulation. Read More

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January 2021

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells .

J Enzyme Inhib Med Chem 2021 Dec;36(1):122-129

Department of Microbiology and Biotechnology, University of Białystok, Białystok, Poland.

Oxythiamine (OT) and 3-deazathiamine (DAT) are the antimetabolites of thiamine. The aim of study was to compare the effects of OT and DAT pyrophosphates (-PP) on the kinetics of mammalian pyruvate dehydrogenase complex (PDHC) and the culture of HeLa cells. The kinetic study showed that 3-deazathiamine pyrophosphate (DATPP) was a much stronger competitive inhibitor ( = 0. Read More

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December 2021

Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.

Mol Cell 2020 10 5;80(2):263-278.e7. Epub 2020 Oct 5.

Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address:

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. Read More

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October 2020

Transcriptomic Analysis of Under the Stress Condition Caused by L. Essential Oil via RNA Sequencing.

Front Microbiol 2020 8;11:1693. Epub 2020 Sep 8.

College of Animal Sciences and Technology, Guangxi University, Nanning, China.

L. essential oil (LCEO) is a natural essential oil with considerable antimicrobial activity, and it can gradually replace some chemical additives in the food industry. However, the genetic evidences of stress response of bacteria under sub-lethal treatment with LCEO is limited. Read More

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September 2020

Expanded roles of pyruvate-sensing PdhR in transcription regulation of the K-12 genome: fatty acid catabolism and cell motility.

Microb Genom 2020 10;6(10)

School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan.

The transcription factor PdhR has been recognized as the master regulator of the pyruvate catabolism pathway in , including both NAD-linked oxidative decarboxylation of pyruvate to acetyl-CoA by PDHc (pyruvate dehydrogenase complex) and respiratory electron transport of NADH to oxygen by Ndh-CyoABCD enzymes. To identify the whole set of regulatory targets under the control of pyruvate-sensing PdhR, we performed genomic SELEX (gSELEX) screening . A total of 35 PdhR-binding sites were identified along the K-12 genome, including previously identified targets. Read More

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October 2020

Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa.

Mol Genet Metab Rep 2020 Sep 22;24:100629. Epub 2020 Jul 22.

National Health Laboratory Service (NHLS), Cape Town, South Africa.

Pyruvate dehydrogenase complex (PDHC) deficiencies are a group of mainly infantile onset disorders stemming from defects in pyruvate catabolism. They are characterised by severe lactic acidosis and progressive neurodegeneration.Although the gene is implicated in most cases of PDHC deficiency worldwide, no pathogenic variants have been reported in South African patients to date, despite availability of sequencing in the state diagnostic setting. Read More

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September 2020

Analysis of the Growth and Metabolites of a Pyruvate Dehydrogenase Complex- Deficient Mutant in a Glycerol-Based Medium.

J Microbiol Biotechnol 2020 May;30(5):753-761

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, P.R. China.

To determine the role of pyruvate dehydrogenase complex (PDHC) in , the growth and metabolism of PDHC-deficient mutant in glycerol-based medium were analyzed and compared with those of other strains. Under aerobic conditions, the PDHC activity was fourfold higher than that of pyruvate formate lyase (PFL), and blocking of PDHC caused severe growth defect and pyruvate accumulation, indicating that the carbon flux through pyruvate to acetyl coenzyme A mainly depended on PDHC. Under anaerobic conditions, although the PDHC activity was only 50% of that of PFL, blocking of PDHC resulted in more growth defect than blocking of PFL. Read More

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Dual Inhibition of Pyruvate Dehydrogenase Complex and Respiratory Chain Complex Induces Apoptosis by a Mitochondria-Targeted Fluorescent Organic Arsenical in vitro and in vivo.

ChemMedChem 2020 03 26;15(6):552-558. Epub 2020 Feb 26.

Department of Chemistry, Wuhan University, Wuhan, 430072, China.

Based on the potential therapeutic value in targeting mitochondria and the fluorophore tracing ability, a fluorescent mitochondria-targeted organic arsenical PDT-PAO-F16 was fabricated, which not only visualized the cellular distribution, but also exerted anti-cancer activity in vitro and in vivo via targeting pyruvate dehydrogenase complex (PDHC) and respiratory chain complexes in mitochondria. In details, PDT-PAO-F16 mainly accumulated into mitochondria within hours and suppressed the activity of PDHC resulting in the inhibition of ATP synthesis and thermogenesis disorder. Moreover, the suppression of respiratory chain complex I and IV accelerated the mitochondrial dysfunction leading to caspase family-dependent apoptosis. Read More

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Inhibition of pyruvate dehydrogenase complex activity by 3-bromopyruvate affects blood platelets responses in type 2 diabetes.

Pharmacol Rep 2020 Feb 10;72(1):225-237. Epub 2020 Jan 10.

Chair of Clinical Biochemistry, Department of Laboratory Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland.

Background: Hyperactivation of blood platelets is an essential factor in the pathomechanism of diabetes-evoked angiopathies. The aim of this work was to investigate whether blood platelets hyperactivation resulting from type 2 diabetic hyperglycaemia-increased pyruvate dehydrogenase complex activity and excessive acetyl-CoA accumulation may be brought to the normal range by the enzyme inhibitors.

Methods: Platelets were isolated from the blood of 9 type 2 diabetic patients and 10 healthy donors. Read More

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February 2020

The N-terminal 1-55 residues domain of pyruvate dehydrogenase from Escherichia coli assembles as a dimer in solution.

Protein Eng Des Sel 2019 12;32(6):271-276

College of Chemistry and Pharmacy, Northwest A&F University, Yangling, China.

The pyruvate dehydrogenase complex (PDHc) from Escherichia coli is a large protein complex consisting of multiple copies of the pyruvate dehydrogenase (E1ec), dihydrolipoamide acetyltransferase (E2ec) and dihydrolipoamide dehydrogenase (E3ec). The N-terminal domain (NTD, residues 1-55) of E1ec plays a critical role in the interaction between E1ec and E2ec and the whole PDHc activity. Using circular dichroism, size-exclusion chromatography and dynamic light scattering spectroscopy, we show that the NTD of E1ec presents dimeric assembly under physiological condition. Read More

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December 2019

Structure optimization and bioactivity evaluation of ThDP analogs targeting cyanobacterial pyruvate dehydrogenase E1.

Bioorg Med Chem 2019 12 28;27(24):115159. Epub 2019 Oct 28.

Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education; College of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address:

Harmful cyanobacteria bloom (HCB) has occurred frequently in recent years and it is urgent to develop novel algicides to deal with this problem. In this paper, a series of novel thiamin diphosphate (ThDP) analogs 5a-5g were designed and synthesized targeting cyanobacterial pyruvate dehydrogenase complex E1 (Cy-PDHc E1). Our results showed that compounds 5a-5g have higher inhibitory activities against Cy-PDHc E1 (IC 9. Read More

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December 2019

Synthesis and Activity of 1,2,3-Triazole Aminopyrimidines against Cyanobacteria as PDHc-E1 Competitive Inhibitors.

J Agric Food Chem 2019 Nov 29;67(45):12538-12546. Epub 2019 Oct 29.

Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry , Central China Normal University , 152 Luoyu Road , Wuhan 430079 , P. R. China.

Cyanobacteria harmful algal blooms are of global concern, but all currently available algicides in the market are nonselective and have potential side effects on nontarget species. In the present work, two series of compounds ( and ) comprising 16 novel 1,2,3-triazole aminopyrimidines were rationally designed and synthesized as control agent for cyanobacteria. Our design focus was the inhibiting cyanobacteria by inhibition against pyruvate dehydrogenase complex E1 (PDHc-E1). Read More

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November 2019

From Africa to Antarctica: Exploring the Metabolism of Fish Heart Mitochondria Across a Wide Thermal Range.

Front Physiol 2019 4;10:1220. Epub 2019 Oct 4.

Département de Biologie, Université du Québec à Rimouski, Rimouski, QC, Canada.

The thermal sensitivity of ectotherms is largely dictated by the impact of temperature on cellular bioenergetics, particularly on mitochondrial functions. As the thermal sensitivity of bioenergetic pathways depends on the structural and kinetic properties of its component enzymes, optimization of their function to different thermal niches is expected to have occurred through selection. In the present study, we sought to characterize mitochondrial phenotypic adjustments to thermal niches in eight ray-finned fish species occupying a wide range of thermal habitats by comparing the activities of key mitochondrial enzymes in their hearts. Read More

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October 2019

Metabolic Flexibility in Cancer: Targeting the Pyruvate Dehydrogenase Kinase:Pyruvate Dehydrogenase Axis.

Mol Cancer Ther 2019 10 11;18(10):1673-1681. Epub 2019 Sep 11.

Department of Urology, University of Kansas Medical Center, Kansas City, Kansas.

Cancer cells use alterations of normal metabolic processes to sustain proliferation indefinitely. Transcriptional and posttranscriptional control of the pyruvate dehydrogenase kinase (PDK) family is one way in which cancer cells alter normal pyruvate metabolism to fuel proliferation. PDKs can phosphorylate and inactivate the pyruvate dehydrogenase complex (PDHC), which blocks oxidative metabolism of pyruvate by the mitochondria. Read More

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October 2019

Enhancement of acetyl-CoA flux for photosynthetic chemical production by pyruvate dehydrogenase complex overexpression in Synechococcus elongatus PCC 7942.

Metab Eng 2020 01 1;57:23-30. Epub 2019 Aug 1.

Laboratory for Bioinformatics, Graduate School of Systems Biosciences, Kyushu University, W5-729, 744, Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. Electronic address:

Genetic manipulation in cyanobacteria enables the direct production of valuable chemicals from carbon dioxide. However, there are still very few reports of the production of highly effective photosynthetic chemicals. Several synthetic metabolic pathways (e. Read More

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January 2020

Comprehensive Profile of Acute Mitochondrial Dysfunction in a Preclinical Model of Severe Penetrating TBI.

Front Neurol 2019 11;10:605. Epub 2019 Jun 11.

Brain Trauma Neuroprotection Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States.

Mitochondria constitute a central role in brain energy metabolism, and play a pivotal role in the development of secondary pathophysiology and subsequent neuronal cell death following traumatic brain injury (TBI). Under normal circumstances, the brain consumes glucose as the preferred energy source for adenosine triphosphate (ATP) production over ketones. To understand the comprehensive picture of substrate-specific mitochondrial bioenergetics responses following TBI, adult male rats were subjected to either 10% unilateral penetrating ballistic-like brain injury (PBBI) or sham craniectomy ( = 5 animals per group). Read More

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The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance.

Autophagy 2019 07 20;15(7):1258-1279. Epub 2019 Feb 20.

b The Key Laboratory of Developmental Genes and Human Disease , Institute of Life Sciences, Southeast University , Nanjing , Jiangsu , China.

Notwithstanding the numerous drugs available for liver cancer, emerging evidence suggests that chemotherapeutic resistance is a significant issue. HGF and its receptor MET play critical roles in liver carcinogenesis and metastasis, mainly dependent on the activity of receptor tyrosine kinase. However, for unknown reasons, all HGF-MET kinase activity-targeted drugs have failed or have been suspended in clinical trials thus far. Read More

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Design, synthesis and biological evaluation of novel inhibitors against cyanobacterial pyruvate dehydrogenase multienzyme complex E1.

Bioorg Med Chem 2019 06 22;27(12):2413-2420. Epub 2019 Jan 22.

Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China. Electronic address:

Cyanobacterial pyruvate dehydrogenase multienzyme complex E1 (PDHc E1) is a potential target enzyme for finding inhibitors to control harmful cyanobacterial blooms. In this study, a series of novel triazole thiamin diphosphate (ThDP) analogs were designed and synthesized by modifying the substituent group of triazole ring and optimizing triazole-benzene linker as potential cyanobacterial PDHc E1 (Cy-PDHc E1) inhibitors. Their inhibitory activities against Cy-PDHc E1 in vitro and algicide activities in vivo were further examined. Read More

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A mitochondria-targeted organic arsenical accelerates mitochondrial metabolic disorder and function injury.

Bioorg Med Chem 2019 03 16;27(5):760-768. Epub 2019 Jan 16.

State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China; College of Chemistry and Chemical Engineering, Hubei Normal University, Huangshi 435002, PR China; Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China. Electronic address:

Considering the vital role of mitochondria in the anti-cancer mechanism of organic arsenical, the mitochondria-targeted precursor PDT-PAO-TPP was designed and synthesized. PDT-PAO-TPP, as a delocalization lipophilic cation (DLCs) which mainly accumulated in mitochondria, contributed to improve anti-cancer efficacy and selectivity towards NB4 cells. In detail, PDT-PAO-TPP inhibited the activity of PDHC resulting in the suppression of ATP synthesis and thermogenesis disorder. Read More

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Alternol eliminates excessive ATP production by disturbing Krebs cycle in prostate cancer.

Prostate 2019 05 20;79(6):628-639. Epub 2019 Jan 20.

Department of Urology, The University of Kansas Medical Center, Kansas City, Kansas.

Background: Alternol is a natural compound isolated from fermentation products of a mutant fungus. Our previous studies demonstrated that Alternol specifically kills cancer cells but spares benign cells.

Methods: To investigate the mechanism underlying alternol-induced cancer cell-specific killing effect, we took a comprehensive strategy to identify Alternol's protein targets in prostate cancer cells, including PC-3, C4-2, and 22RV1, plus benign BPH1 cell lines. Read More

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Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the αV138M variant of human pyruvate dehydrogenase.

J Biol Chem 2018 08 3;293(34):13204-13213. Epub 2018 Jul 3.

From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,

The pyruvate dehydrogenase multienzyme complex (PDHc) connects glycolysis to the tricarboxylic acid cycle by producing acetyl-CoA via the decarboxylation of pyruvate. Because of its pivotal role in glucose metabolism, this complex is closely regulated in mammals by reversible phosphorylation, the modulation of which is of interest in treating cancer, diabetes, and obesity. Mutations such as that leading to the αV138M variant in pyruvate dehydrogenase, the pyruvate-decarboxylating PDHc E1 component, can result in PDHc deficiency, an inborn error of metabolism that results in an array of symptoms such as lactic acidosis, progressive cognitive and neuromuscular deficits, and even death in infancy or childhood. Read More

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Simultaneous Measurement of Superoxide/Hydrogen Peroxide and NADH Production by Flavin-containing Mitochondrial Dehydrogenases.

J Vis Exp 2018 02 24(132). Epub 2018 Feb 24.

Department of Biochemistry, Memorial University of Newfoundland.

It has been reported that mitochondria can contain up to 12 enzymatic sources of reactive oxygen species (ROS). A majority of these sites include flavin-dependent respiratory complexes and dehydrogenases that produce a mixture of superoxide (O2) and hydrogen peroxide (H2O2). Accurate quantification of the ROS-producing potential of individual sites in isolated mitochondria can be challenging due to the presence of antioxidant defense systems and side reactions that also form O2/H2O2. Read More

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February 2018

Thiamine Responsive Pyruvate Dehydrogenase Complex Deficiency: A Potentially Treatable Cause of Leigh's Disease.

J Pediatr Neurosci 2017 Jul-Sep;12(3):265-267

Department of Pediatrics, Pediatric Neurology and Neurodevelopment Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Pyruvate dehydrogenase complex (PDHC) deficiency is a rare metabolic disorder that affects tissues with high energy demand such as the central nervous system. The clinico-radiological phenotype of Leigh's disease is one of its common presentations. We present a 9-month-old boy with rapidly progressive infantile Leigh's disease. Read More

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December 2017

Synthesis and herbicidal activity of optically active α-(substituted phenoxyacetoxy) (substituted phenyl) methylphosphonates.

Pestic Biochem Physiol 2017 Nov 27;143:298-305. Epub 2016 Nov 27.

Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, PR China. Electronic address:

α-(Substituted phenoxyacetoxy) alkylphosphonates containing one chiral carbon atom have been demonstrated to be PDHc inhibitor with good herbicidal activity and some of them could be used as potential herbicide. In order to determine any difference in herbicidal activities between (R) and (S) isomers, the synthetic method of optically active substituted phenylalkylphosphonates IB were explored. A highly practical, enantioselective hydrophosphonylation was developed to prepare optically active O,O-dimethyl α-hydroxyalkylphosphonates 3 as key intermediate by asymmetric addition reaction of dimethylphosphite 1 and several kinds of aldehydes 2 using tridentate Schiff base Al(III) complexes as catalysts. Read More

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November 2017

Design and synthesis of highly selective pyruvate dehydrogenase complex E1 inhibitors as bactericides.

Bioorg Med Chem 2018 01 13;26(1):84-95. Epub 2017 Nov 13.

Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China.

In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. Read More

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January 2018