Search results for: Galina Florova

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Molecular mechanism of two nanobodies that inhibit PAI‐1 activity reveals a modulation at distinct stages of the PAI‐1/plasminogen activator interaction

Machteld Sillen, Stephen D. Weeks, Xiaohua Zhou, Andrey A. Komissarov, more

Journal of Thrombosis and Haemostasis > 18 > 3 > 681 - 692

Background Plasminogen activator inhibitor‐1 (PAI‐1), a key inhibitor of plasminogen activators (PAs) tissue‐type PA (tPA) and urokinase‐type PA (uPA) plays a crucial role in many (patho)physiological processes (e.g., cardiovascular disease, tissue fibrosis) as well as in many age‐related pathologies. Therefore, much effort has been put into the development of small molecule or antibody‐based PAI‐1...

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Increased expression of plasminogen activator inhibitor-1 (PAI-1) is associated with depression and depressive phenotype in C57Bl/6J mice

René A. Girard, Prashant S. Chauhan, Torry A. Tucker, Tim Allen, more

Experimental Brain Research > 2019 > 237 > 12 > 3419-3430

Plasminogen activator inhibitor 1 (PAI-1), which is elevated in numerous disease states, has been implicated as a stress-related protein involved in the pathogenesis of depression. We measured PAI-1 in the plasma of healthy and depressed individuals and assessed plasminogen activator (PA) expression and regulation by PAI-1 in cultured normal human astrocytes (NHA). Elevated plasma PAI-1 levels were...

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Lack of durable protection against cotton smoke-induced acute lung injury in sheep by nebulized single chain urokinase plasminogen activator or tissue plasminogen activator

Satoshi Fukuda, Perenlei Enkhbaatar, Christina Nelson, Robert A. Cox, more

Clinical and Translational Medicine > 2018 > 7 > 1 > 1-13

Background Airway fibrin casts are clinically important complications of severe inhalational smoke-induced acute lung injury (ISIALI) for which reliable evidence-based therapy is lacking. Nebulized anticoagulants or a tissue plasminogen activator; tPA, has been advocated, but airway bleeding is a known and lethal potential complication. We posited that nebulized delivery of single chain urokinase...

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Organizing empyema induced in mice by Streptococcus pneumoniae: effects of plasminogen activator inhibitor-1 deficiency

Torry A. Tucker, Ann Jeffers, Jake Boren, Brandon Quaid, more

Clinical and Translational Medicine > 2016 > 5 > 1 > 1-18

Background Pleural infection affects about 65,000 patients annually in the US and UK. In this and other forms of pleural injury, mesothelial cells (PMCs) undergo a process called mesothelial (Meso) mesenchymal transition (MT), by which PMCs acquire a profibrogenic phenotype with increased expression of α-smooth muscle actin (α-SMA) and matrix proteins. MesoMT thereby contributes to pleural organization...

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Structural and Stereochemical Analysis of a Modular Polyketide Synthase Ketoreductase Domain Required for the Generation of a cis-Alkene

Shilah A. Bonnett, Jonathan R. Whicher, Kancharla Papireddy, Galina Florova, more

Chemistry & Biology > 2013 > 20 > 6 > 772-783

The formation of an activated cis-3-cyclohexylpropenoic acid by Plm1, the first extension module of the phoslactomycin polyketide synthase, is proposed to occur through an L-3-hydroxyacyl-intermediate as a result of ketoreduction by an A-type ketoreductase (KR). Here, we demonstrate that the KR domain of Plm1 (PlmKR1) catalyzes the formation of an L-3-hydroxyacyl product. The crystal structure of...

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Streptomyces coelicolor RedP and FabH enzymes, initiating undecylprodiginine and fatty acid biosynthesis, exhibit distinct acyl‐CoA and malonyl‐acyl carrier protein substrate specificities

Renu Singh, SangJoon Mo, Galina Florova, Kevin A. Reynolds

FEMS Microbiology Letters > 328 > 1 > 32 - 38

RedP is proposed to initiate undecylprodiginine biosynthesis in Streptomyces coelicolor by condensing an acyl‐CoA with malonyl‐ACP and is homologous to FabH that catalyzes the same reaction for initiation of fatty acid biosynthesis. Herein, we report the substrate specificities of RedP and FabH from assays using pairings of two acyl‐CoA substrates (acetyl‐CoA and isobutyryl‐CoA) and two malonyl‐ACP...

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High titer production of tetracenomycins by heterologous expression of the pathway in a Streptomyces cinnamonensis industrial monensin producer strain

Chaoxuan Li, Chris Hazzard, Galina Florova, Kevin A. Reynolds

Metabolic Engineering > 2009 > 11 > 6 > 319-327

Streptomyces cinnamonensis C730.1 and C730.7, are industrially mutagenized strains that produce moderate and high levels of the polyketide polyether antibiotic monensin A, respectively, in an oil-based fermentation medium. The possibility that these strains could be used for high titer production of a heterologous polyketide product was investigated by expression of the entire tetracenomycin (TCM)...

article

Alkyl-CoA Disulfides as Inhibitors and Mechanistic Probes for FabH Enzymes

Mamoun M. Alhamadsheh, Faik Musayev, Andrey A. Komissarov, Sarbjot Sachdeva, more

Chemistry & Biology > 2007 > 14 > 5 > 513-524

The first step of the reaction catalyzed by the homodimeric FabH from a dissociated fatty acid synthase is acyl transfer from acyl-CoA to an active site cysteine. We report that C ₁ to C ₁₀ alkyl-CoA disulfides irreversibly inhibit Escherichia coli FabH (ecFabH) and Mycobacterium tuberculosis FabH with relative efficiencies that reflect these enzymes' differential acyl-group specificity...

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Synthesis and biological evaluation of thiazolidine-2-one 1,1-dioxide as inhibitors of Escherichia coli β-ketoacyl-ACP-synthase III (FabH)

Mamoun M. Alhamadsheh, Norman C. Waters, Donald P. Huddler, Mara Kreishman-Deitrick, more

Bioorganic & Medicinal Chemistry Letters > 2007 > 17 > 4 > 879-883

A series of cyclic sulfones has been synthesized and their activity against β-ketoacyl-ACP-synthase III (FabH) has been investigated. The compounds are selectively active against Escherichia coli FabH (ecFabH), but not Mycobacterium tuberculosis FabH (mtFabH) or Plasmodium falciparum KASIII (PfKASIII). The activity against ecFabH ranges from 0.9 to >100μM and follows a consistent general SAR trend...

article

Multiple pathways for acetate assimilation in Streptomyces cinnamonensis

Konstantin Akopiants, Galina Florova, Chaoxuan Li, Kevin A. Reynolds

Journal of Industrial Microbiology & Biotechnology > 2006 > 33 > 2 > 141-150

In most bacteria acetate assimilation is accomplished via the glyoxylate pathway. Isocitrate lyase (ICL) and malate synthase (MS) are two key enzymes of this pathway, which results in the net generation of one molecule of succinyl-CoA from two acetyl-CoA molecules. Genetic and biochemical data have shown that genes encoding these key enzymes are present in streptomycetes, yet there has been no clear...

article

An Unexpected Interaction between the Modular Polyketide Synthases, Erythromycin DEBS1 and Pikromycin PikAIV, Leads to Efficient Triketide Lactone Synthesis ^†

Beom Seok Kim, T. Ashton Cropp, Galina Florova, Yuko Lindsay, more

Biochemistry > 2002 > 41 > 35 > 10827 - 10833

article

Enzymes Involved in Fatty Acid and Polyketide Biosynthesis in Streptomyces glaucescens : Role of FabH and FabD and Their Acyl Carrier Protein Specificity ^†

Galina Florova, Galina Kazanina, Kevin A. Reynolds

Biochemistry > 2002 > 41 > 33 > 10462 - 10471

article

A Streptomyces collinus Thiolase with Novel Acetyl-CoA:Acyl Carrier Protein Transacylase Activity ^† ^, ^‡

Sandra Lobo, Galina Florova, Kevin A. Reynolds

Biochemistry > 2001 > 40 > 39 > 11955 - 11964

article

Polyketide synthase acyl carrier protein (ACP) as a substrate and a catalyst for malonyl ACP biosynthesis

Pei Zhou, Galina Florova, Kevin A Reynolds

Chemistry & Biology > 1999 > 6 > 8 > 577-584

Using an acyl-acyl carrier protein (ACP) as a starter unit, type II polyketide synthases (PKSs) generate a wide range of polyketide products by successive decarboxylative condensations with the two-carbon donor malonyl (ACP). In vitro experiments have demonstrated that polyketide biosynthesis in reconstituted PKS systems requires the fatty acid synthase (FAS) enzyme malonyl CoA:ACP acyltransferase...

article

Cloning, Expression, and Characterization of a Type II 3-Dehydroquinate Dehydratase Gene fromStreptomyces hygroscopicus

Galina Florova, Claudio D. Denoya, Margaret R. Morgenstern, Deborah D. Skinner, more

Archives of Biochemistry and Biophysics > 1998 > 350 > 2 > 298-306

A gene encoding dehydroquinate dehydratase (DHQase) was cloned fromStreptomyces hygroscopicusvar.ascomyceticus.The 528-bp open reading frame specified a primary translation product of 175 amino acids with a calculatedM _r of 18,789. The predicted amino acid sequence of the DHQase showed similarities to bacterial and fungal type II DHQases. Overexpression of thedhqgene was accomplished inEscherichia...

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