8,726 results match your criteria dihydrofolate reductase


Live-Cell Protein Modification by Boronate-Assisted Hydroxamic Acid Catalysis.

J Am Chem Soc 2021 Sep 10;143(37):14976-14980. Epub 2021 Sep 10.

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113-0033.

Selective methods for introducing protein post-translational modifications (PTMs) within living cells have proven valuable for interrogating their biological function. In contrast to enzymatic methods, abiotic catalysis should offer access to diverse and new-to-nature PTMs. Herein, we report the boronate-assisted hydroxamic acid (BAHA) catalyst system, which comprises a protein ligand, a hydroxamic acid Lewis base, and a diol moiety. Read More

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September 2021

Folic Acid Absorption Characteristics and Effect on Cecal Microbiota of Laying Hens.

Front Vet Sci 2021 17;8:720851. Epub 2021 Aug 17.

Laboratory of Poultry Production, College of Animal Science, Shanxi Agricultural University, Jinzhong, China.

This experiment was conducted to investigate the characteristics of folic acid (FA) absorption in laying hens and the effect of FA supplementation on cecal microbiota. A total of 432 healthy hens (30-week-old) were randomly assigned to four diets supplemented with FA: 0, 1, 6, and 24 mg/kg of feed for 8 w. Blood, duodenum, jejunum, ileum, cecum, and cecal chyme samples (six samples per treatment) were collected from the hens at the end of the feeding trial. Read More

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Comparison of recovery characteristics between AnAOB and AOB-AnAOB granular sludge after long-term storage.

Sci Total Environ 2021 Aug 25;802:149741. Epub 2021 Aug 25.

Key Laboratory of Urban Stormwater System and Water Environment, Ministry of Education, Beijing University of Civil Engineering and Architecture, Beijing 100044, China. Electronic address:

The recovery characteristics of long-term stored sludge are still elusive. Here, an AnAOB granular sludge reactor (R1) (15 d) was found to recover faster than AOB-AnAOB granular sludge reactor (R2) (21 d) after 240 d 4 °C storage. Higher nitrogen removal performance was also achieved in R1 (5. Read More

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Decreased susceptibility to dihydrofolate reductase inhibitors associated with genetic polymorphisms in Ugandan Plasmodium falciparum isolates.

J Infect Dis 2021 Aug 30. Epub 2021 Aug 30.

University of California, San Francisco, CA, USA.

Background: The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug susceptibility data for P. falciparum field isolates are limited. Read More

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Adaptations for Pressure and Temperature in Dihydrofolate Reductases.

Microorganisms 2021 Aug 11;9(8). Epub 2021 Aug 11.

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

Enzymes from extremophilic microbes that live in extreme conditions are generally adapted so that they function under those conditions, although adaptations for extreme temperatures and pressures can be difficult to unravel. Previous studies have shown mutation of Asp27 in dihydrofolate reductase (DHFR) to Glu27 in (Mp). DHFR enhances activity at higher pressures, although this may be an adaptation for cold. Read More

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Role of Active Site Loop Dynamics in Mediating Ligand Release from Dihydrofolate Reductase.

Biochemistry 2021 Sep 24;60(35):2663-2671. Epub 2021 Aug 24.

Department of Integrative Structural and Computational Biology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

Conformational fluctuations from ground-state to sparsely populated but functionally important excited states play a key role in enzyme catalysis. For dihydrofolate reductase (DHFR), the release of the product tetrahydrofolate (THF) and oxidized cofactor NADP occurs through exchange between closed and occluded conformations of the Met20 loop. A "dynamic knockout" mutant of DHFR, where the sequence in the Met20 loop is replaced by the human sequence (N23PP/S148A), models human DHFR and is incapable of accessing the occluded conformation. Read More

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September 2021

Enhancement of anti-TNFα monoclonal antibody production in CHO cells through the use of UCOE and DHFR elements in vector construction and the optimization of cell culture media.

Prep Biochem Biotechnol 2021 Aug 24:1-19. Epub 2021 Aug 24.

Department of Animal Biotechnology, Institute of Tropical Biology, Vietnam Academy of Science and Technology, Ho Chi Minh City, Vietnam.

Recently, there has been a high demand for anti-tumor necrosis factor-α monoclonal antibodies (mAbTNFα) in the treatment of rheumatoid arthritis and other autoimmune diseases. Thus, efficient strategies and stable high-producing cell lines need to be established to increase antibody production. In this study, we describe an efficient approach to establish a mAbTNFα high-producing clone through the optimization of expression vectors and cell culture media. Read More

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Phytochemical constituents of as potential inhibitors of dihydrofolate reductase: A strategic approach against shigellosis.

J Biomol Struct Dyn 2021 Aug 23:1-16. Epub 2021 Aug 23.

Faculty of Arts and Sciences, Department of Chemistry, Gaziantep University, Gaziantep, Turkey.

type 1 is considered as an epidemic in different developing countries, which is responsible for the most severe form of bacterial dysentery. It habitually can develop to the most severe form of dysentery with deadly complications. Development of drugs against this disease is still ongoing. Read More

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Targeted Mitochondrial Fluorescence Imaging-Guided Tumor Antimetabolic Therapy with the Imprinted Polymer Nanomedicine Capable of Specifically Recognizing Dihydrofolate Reductase.

ACS Appl Mater Interfaces 2021 Sep 19;13(34):40332-40341. Epub 2021 Aug 19.

State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China.

As we all know, inhibiting the activity of dihydrofolate reductase (DHFR) has always been an effective strategy for folate antimetabolites to treat tumors. In the past, it mainly relied on chemical drugs. Here, we propose a new strategy, (3-propanecarboxyl)triphenylphosphonium bromide (CTPB)-modified molecularly imprinted polymer nanomedicine (MIP-CTPB). Read More

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September 2021

A proline metabolism selection system and its application to the engineering of lipid biosynthesis in Chinese hamster ovary cells.

Metab Eng Commun 2021 Dec 27;13:e00179. Epub 2021 Jul 27.

Industrial Biotechnology Centre, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.

Chinese hamster ovary (CHO) cells are the leading mammalian cell host employed to produce complex secreted recombinant biotherapeutics such as monoclonal antibodies (mAbs). Metabolic selection marker technologies (e.g. Read More

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December 2021

Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy.

Comput Struct Biotechnol J 2021 8;19:4059-4066. Epub 2021 Jul 8.

Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain.

The development of resistance to chemotherapeutic agents, such as Doxorubicin (DOX) and cytarabine (AraC), is one of the greatest challenges to the successful treatment of Acute Myeloid Leukemia (AML). Such acquisition is often underlined by a metabolic reprogramming that can provide a therapeutic opportunity, as it can lead to the emergence of vulnerabilities and dependencies to be exploited as targets against the resistant cells. In this regard, genome-scale metabolic models (GSMMs) have emerged as powerful tools to integrate multiple layers of data to build cancer-specific models and identify putative metabolic vulnerabilities. Read More

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The Resistome and Mobilome of Multidrug-Resistant Staphylococcus sciuri C2865 Unveil a Transferable Trimethoprim Resistance Gene, Designated , Spread Unnoticed.

mSystems 2021 Aug 10;6(4):e0051121. Epub 2021 Aug 10.

Evolutionary Genomics Group, División de Microbiología, Universidad Miguel Hernández, San Juan, Alicante, Spain.

Methicillin-resistant Staphylococcus sciuri (MRSS) strain C2865 from a stranded dog in Nigeria was trimethoprim (TMP) resistant but lacked formerly described staphylococcal TMP-resistant dihydrofolate reductase genes (). Whole-genome sequencing, comparative genomics, and pan-genome analyses were pursued to unveil the molecular bases for TMP resistance via resistome and mobilome profiling. MRSS C2865 comprised a species subcluster and positioned just above the intraspecies boundary. Read More

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Comparative EPR Study on the Scavenging Effect of Methotrexate with the Isomers of Its Photoswitchable Derivative.

Pharmaceuticals (Basel) 2021 Jul 11;14(7). Epub 2021 Jul 11.

Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pécs, Szigeti 12, H-7624 Pécs, Hungary.

The scavenging effect of the antimetabolite dihydrofolate reductase inhibitor methotrexate (MTX) and the isomers of its photoswitchable derivate, - and -phototrexate (PHX), have been compared by ESR spectroscopy, with the application of a cyclic hydroxylamine spin probe. The results showed the most pronounced scavenging effect in the presence of -phototrexate (-PHX). At a low concentration (100 µM) -PHX also showed a greater scavenging effect than the parent molecule MTX. Read More

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The 5-formyl-tetrahydrofolate proteome links folates with C/N metabolism and reveals feedback regulation of folate biosynthesis.

Plant Cell 2021 Aug 5. Epub 2021 Aug 5.

CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China.

Folates are indispensable for plant development, but their molecular mode of action remains elusive. We synthesized a probe, '5-F-THF-Dayne', comprising 5-formyl-tetrahydrofolate coupled to a photoaffinity tag. Exploiting this probe in an affinity proteomics study in Arabidopsis thaliana, we retrieved 51 hits. Read More

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ecRESCUE: a novel ecDHFR-regulated RESCUE system with reduced RNA off-targeting activity.

Cell Commun Signal 2021 Jul 31;19(1):81. Epub 2021 Jul 31.

National Research Institute for Family Planning, Beijing, 100081, China.

The currently available RESCUE RNA base editing system demonstrates considerable potential for the treatment of genetic diseases at the transcriptional level. However, the relatively high incidence of off-target events hampers the precise RNA editing, thereby limiting its use in the clinical setting. This study describes a new RNA base editing method, named ecRESCUE, which utilizes inducible stabilization of the protein ecDHFR DD fused at the C-terminal of the original RESCUE system. Read More

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Characterization of newly established Pralatrexate-resistant cell lines and the mechanisms of resistance.

BMC Cancer 2021 Jul 31;21(1):879. Epub 2021 Jul 31.

Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

Background: Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance.

Methods: To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. Read More

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3-Methyl-imidazo[2,1-b]thiazole derivatives as a new class of antifolates: Synthesis, in vitro/in vivo bio-evaluation and molecular modeling simulations.

Bioorg Chem 2021 Oct 24;115:105205. Epub 2021 Jul 24.

Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.. Electronic address:

Inhibiting the Dihydrofolate reductase (DHFR) enzyme has been validated in multiple clinical manifestations related to bacterial infection, malaria, and multiple types of cancer. Herein, novel series of 3-methyl-imidazo[2,1-b] thiazole-based analogs were synthesized and biologically evaluated for their in vitro inhibitory profile towards DHFR. Compounds 22 and 23 exhibited potent inhibitory profile targeting DHFR (IC 0. Read More

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October 2021

Unlocking the bacterial membrane as a therapeutic target for next-generation antimicrobial amphiphiles.

Mol Aspects Med 2021 Jul 26:100999. Epub 2021 Jul 26.

Laboratory of Nanotechnology and Chemical Biology, Regional Center for Biotechnology, Faridabad, Haryana, 121001, India. Electronic address:

Gram-positive bacteria like Enterococcus faecium and Staphylococcus aureus, and Gram-negative bacteria like Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter Spp. are responsible for most of fatal bacterial infections. Bacteria present a handful of targets like ribosome, RNA polymerase, cell wall biosynthesis, and dihydrofolate reductase. Read More

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Novel Ag/cellulose-doped CeO quantum dots for efficient dye degradation and bactericidal activity with molecular docking study.

Carbohydr Polym 2021 Oct 17;269:118346. Epub 2021 Jun 17.

Department of Physics, Riphah Institute of Computing and Applied Sciences (RICAS), Riphah International University, 14 Ali Road, Lahore, Pakistan.

In the present study, the novel Ag/cellulose nanocrystal (CNC)-doped CeO quantum dots (QDs) with highly efficient catalytic performance were synthesized using one pot co-precipitation technique, which were then applied in the degradation of methylene blue and ciprofloxacin (MBCF) in wastewater. Catalytic activity against MBCF dye was significantly reduced (99.3%) for (4%) Ag dopant concentration in acidic medium. Read More

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October 2021

Development of antibacterial compounds that constrain evolutionary pathways to resistance.

Elife 2021 07 19;10. Epub 2021 Jul 19.

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.

Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of dihydrofolate reductase (DHFR). Read More

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Investigation of reactive properties, adsorption on fullerene, DFT, molecular dynamics simulation of an anthracene derivative targeting dihydrofolate reductase and human dUTPase.

J Biomol Struct Dyn 2021 Jul 19:1-10. Epub 2021 Jul 19.

Department of Chemistry, Faculty of Science, University of Jiroft, Jiroft, Iran.

Anthracenes are aromatic compounds with flexible structure and reactivity which are of great interest to theoretical and experimental chemists. Theoretical investigations of 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione (Mitoxantrone) (DDEA) based on density functional theory, molecular dynamics and adsorption on fullerene are reported in the present research. The suitable situation for adsorption with fullerene (C60) is the cyclohex-2-ene-1,4-dione ring of DDEA. Read More

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Fitness of sulfadoxine-resistant Plasmodium berghei harboring a single mutation in dihydropteroate synthase (DHPS).

Acta Trop 2021 Oct 15;222:106049. Epub 2021 Jul 15.

Department of Tropical Medicine and Parasitology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. Electronic address:

Genetic changes conferring drug resistance are generally believed to impose fitness costs to pathogens in the absence of the drug. However, the fitness of resistant parasites against sulfadoxine/pyrimethamine has been inconclusive in Plasmodium falciparum. This is because resistance is conferred by the complex combination of mutations in dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr), which makes it difficult to separately assess the extent and magnitude of the costs imposed by mutations in dhps and dhfr. Read More

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October 2021

An overview of three biocatalysts of pharmaceutical importance synthesized by microbial cultures.

AIMS Microbiol 2021 27;7(2):124-137. Epub 2021 Apr 27.

Biomedical Sciences Research Institute, Ulster University, Coleraine Northern Ireland, UK.

This article includes a general overview of the published research on a topic relevant to biomedical sciences research, pharma-industries and healthcare sector. We have presented a concise information on three enzymes. These biomolecules have been investigated for their biocatalytic activities beneficial in the detection of drugs and their metabolites present in micro-quantities in samples of blood, urine, and other body fluids, such as salicylate hydroxylase, and dihydrofolate reductase. Read More

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Polymorphism of Antifolate Drug Resistance in From Local Residents and Migrant Workers Returned From the China-Myanmar Border.

Front Cell Infect Microbiol 2021 24;11:683423. Epub 2021 Jun 24.

Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, China.

Drug-resistant  malaria impedes efforts to control, eliminate, and ultimately eradicate malaria in Southeast Asia. resistance to antifolate drugs derives from point mutations in specific parasite genes, including the dihydropteroate synthase (), dihydrofolate reductase (), and GTP cyclohydrolase I () genes. This study aims to investigate the prevalence and spread of drug resistance markers in populating the China-Myanmar border. Read More

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Influence of solution ionic strength on the stabilities of M20 loop conformations in apo E. coli dihydrofolate reductase.

J Chem Phys 2021 May;154(19):195103

Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.

Interactions among ions and their specific interactions with macromolecular solutes are known to play a central role in biomolecular stability. However, similar effects in the conformational stability of protein loops that play functional roles, such as binding ligands, proteins, and DNA/RNA molecules, remain relatively unexplored. A well-characterized enzyme that has such a functional loop is Escherichia coli dihydrofolate reductase (ecDHFR), whose so-called M20 loop has been observed in three ordered conformations in crystal structures. Read More

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Comparison of Associations between One-Carbon Metabolism, Lipid Metabolism, and Fatty Liver Markers in Normal-Weight and Overweight People Aged 20-40 Years.

Ann Nutr Metab 2021 Jul 7:1-10. Epub 2021 Jul 7.

Department of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland.

The aim of the present study was to compare biomarkers of one-carbon metabolism (OCM), lipid metabolism, and fatty liver in people with normal and increased body weight. The study was performed on 421 participants, aged 20-40 years, enrolled in Poznan, Poland, in 2016-2018. Choline and betaine intakes were assessed. Read More

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Chemogenetic Control of Protein Localization and Mammalian Cell Signaling by SLIPT.

Methods Mol Biol 2021 ;2312:237-251

Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Showa-ku, Nagoya, Japan.

Chemical control of protein localization is a powerful approach for manipulating mammalian cellular processes. Self-localizing ligand-induced protein translocation (SLIPT) is an emerging platform that enables control of protein localization in living mammalian cells using synthetic self-localizing ligands (SLs). We recently established a chemogenetic SLIPT system, in which any protein of interest fused to an engineered variant of Escherichia coli dihydrofolate reductase, DHFR, can be rapidly and specifically translocated from the cytoplasm to the inner leaflet of the plasma membrane (PM) using a trimethoprim (TMP)-based PM-targeting SL, mcTMP. Read More

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Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Pteridine Reductase and Dihydrofolate Reductase.

Pharmaceuticals (Basel) 2021 Jun 30;14(7). Epub 2021 Jun 30.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

and parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to (), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. Read More

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New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action.

Antibiotics (Basel) 2021 Jun 12;10(6). Epub 2021 Jun 12.

Laboratory of Molecular Microbiology & Antimicrobials, Department of Pathology & Experimental Therapeutics, Medical School, University of Barcelona, Bellvitge Institute for Biomedical Research (IDIBELL), Hospitalet de Llobregat, 08907 Barcelona, Spain.

This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds and ) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk diffusion assays on Petri dishes, compounds and showed synergistic effects with colistin. Read More

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Minimal peptide length required to span the mitochondrial protein translocases in Trypanosoma brucei.

Mol Biochem Parasitol 2021 07 29;244:111393. Epub 2021 Jun 29.

Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestr. 3, CH-3012, Bern, Switzerland. Electronic address:

Mitochondrial protein import depends on heterooligomeric translocases in the outer and inner membranes. Using import substrates consisting of various lengths of the N-terminal part of mitochondrial dihydrolipoamide dehydrogenase (LDH) fused to dihydrofolate reductase we present an in vivo analysis showing that in Trypanosoma brucei at least 96 aa of mature LDH are required to efficiently produce an import intermediate that spans both translocases. This is different to yeast, where around 50 aa are sufficient to achieve the same task and likely reflects the different arrangement and architecture of the trypanosomal mitochondrial translocases. Read More

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