DOCSLIB.ORG

Synthesis and Antifungal Properties of Compounds Which Target the Α-Aminoadipate Pathway ORIGINAL ARTICLES

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis and Antifungal Properties of Compounds Which Target the Α-Aminoadipate Pathway ORIGINAL ARTICLES ORIGINAL ARTICLES Department of Chemistry 1 and Department of Biology2, University of Saskatchewan, Canada Synthesis and antifungal properties of compounds which target the a-aminoadipate pathway D. R. J. Palmer,1 H. Balogh,1 G. Ma,1 X. Zhou,1 M. Marko,1 S. G. W. Kaminskyj 2 Received June 20, 2003, accepted July 22, 2003 Susan G. W. Kaminskyj, Department of Biology, University of Saskatchewan, 112 Science Place, Saskatoon, Saskatchewan Canada S7N 5E2. [email protected] Pharmazie 59: 93–98 (2004) Fungi synthesize lysine via the a-aminoadipate pathway, which is not found in plants or animals. This pathway has been proposed as a target for antifungal agents, but until now no reports have appeared to test this proposal. Hampering studies on the susceptibility of filamentous fungi such as those of the clinically important genus Aspergillus is the fact that growth quantitation is notoriously difficult. We have used the recently-reported XTT-based method of biomass quantitation to measure the suscept- ibility of Aspergillus nidulans strain A28 to growth suppression by novel compounds designed to target early steps in the a-aminoadipate lysine biosynthesis pathway, specifically those steps involving (R)- homocitrate and (2R,3S)-homoisocitrate. Three compounds show moderate inhibition of fungal growth, which can be partially restored by the presence of lysine in the growth medium. 1. Introduction All higher fungi synthesize lysine via the a-aminoadipate pathway (Zabriskie and Jackson 2000), which is not found Invasive fungal infections are a severe threat to human in plants or animals. This pathway could therefore serve health: untreated, mortality rates from systemic fungal infections typically exceed 98%. Fungal spores are ubi- as a target for antifungal compounds since its disruption quitous; for example, there are 1–100 pathogenic Asper- should not affect the metabolism of host organisms gillus fumigatus spores per m3, worldwide (Latge´ 2001). (Suvarna et al. 1998). However, no studies have appeared Our main defense against systemic fungal infections is a reporting the use of this target for the design of anti- healthy immune response; thus it is not surprising that fungal compounds. We now report the synthesis of a series these are the primary AIDS-defining infections in HIV-po- of compounds that target enzymes from the a-amino- sitive people (Walsh and Groll 1999), and that they are adipate pathway, and an investigation of their antifungal the scourge of other immunocompromised individuals behavior. including transplant patients and those with autoimmune The early steps of the a-aminoadipate pathway are shown disease. in Scheme 1. While all the metabolites are known, not all The treatment for systemic fungal infections can be toxic of the enzymes responsible for these transformations have in its own right (Ugur et al. 2002), because most of these been identified (Zabriskie and Jackson 2000). Specifically, drugs target ergosterol or its biosynthesis, and so also af- the conversion of (R)-homocitrate to cis-homoaconitate fect cholesterol, which is an essential component of mam- has not been assigned to a gene product. It may be that malian membranes. These treatments are expensive, aver- (R)-homocitrate is converted to (2R,3S)-homoisocitrate by aging in excess of US$30,000 per patient per incident a single enzyme, in simile with the reaction catalyzed by (Wilson et al. 2002). Despite intensive treatment with cur- aconitase shown in Scheme 2. Indeed, homoaconitate rently-available antifungal agents, permanent cures are un- hydratase, or homoaconitase, is clearly related to aconitase common, such that survival/cure rates after systemic fun- in sequence, and most likely in structure (Irvin and gal infection are often expressed only for the following Bhattacharjee 1998). However, neither the homoaconitate six-month period, and many patients remain on long-term hydratase from Saccharomyces cerevisiae (LYS4) nor prophylactic antifungal therapy. In addition, fungi are also Aspergillus nidulans (LysF) has been reported to catalyze severe agricultural pests, causing damage to all crops (e. g. the dehydration of (R)-homocitrate (Gamonet and Laquin Barnes 1979, Howlett et al. 2001) and stored agricultural 1998, Weidner et al. 1997). This somewhat counter- products. These facts, coupled with increasing incidence intuitive phenomenon is a subject of interest in our labora- of antibiotic (Alexander and Perfect 1997) and antifungal tory. (Loeffler and Stevens 2003; Vanden Bossche et al. 2003) Regardless of the identity of the catalyst that dehydrates resistance indicate that new antimicrobial strategies should (R)-homocitrate, a rational approach to the inhibition of steps be pursued constantly. of the pathway involving (R)-homocitrate and (2R,3S)- Pharmazie 59 (2004) 2 93 ORIGINAL ARTICLES Scheme 1 O CO - CO - - 2 - 2 + NADH CO2 CO2 NAD SCoA H H H OH +CO2 O -CoASH -H O CO - + - 2 2 +H2O CO2 -O2C OH -O2C H H H O H H H H H H i ii iii iv H H H H H H H H H H CO - CO - CO - - - 2 2 2 CO2 CO2 The first steps of the a-aminoadipate pathway: i.) homocitrate synthase; ii.) unidentified enzyme; iii.) homoaconitate hydratase (or homoaconitase); iv.) homoisocitrate dehydrogenase Scheme 2 CO - CO - 2 CO - 2 -H O+H2 O H H 2 - 2 H OH CO2 -O2C OH -O2C H H H H H H H - - - CO2 CO2 CO2 The reaction sequence catalyzed by aconitase homoisocitrate can be taken. Specifically, compounds de- been developed by Meletiadis et al. (2001) that they report signed to mimic the structure of the metabolites of interest correlates well with visible mycelial growth in several could inhibit homoaconitase and/or homoisocitrate dehydro- Aspergillus species. genase, resulting in an impairment in lysine biosynthesis. A variety of carboxyalkyl- and carboxyaryl-substituted d- One of the considerations in the design is that the com- malic acids and their corresponding methyl esters were de- pounds not be effective aconitase inhibitors: such com- signed as analogues of (R)-homocitrate and (2R,3S)-homoi- pounds are extremely toxic (Peters and Shorthouse 1971, socitrate. Syntheses of these compounds rely on a diastereo- Lauble et al. 1996). Therefore the difference between sub- selective alkylation to give an optically active product. strates for aconitase and homoaconitase, namely the pre- These compounds were tested for their ability to impair the sence of a propionate rather than an acetate moiety, growth of Aspergillus nidulans A28 in minimal media (i.e. should be retained or even exaggerated in any putative in the absence of exogenous lysine) and in rich media sup- antifungal. plemented with excess lysine. Of these, only methyl esters Fungal species employ two major growth morphologies: 1b–3b showed inhibitory effects on fungal growth. they form colonies of single cells called yeasts, or pro- duce multicellular filamentous mycelia. Some human fun- 2. Investigations and results gal pathogens, such as Candida albicans, are dimorphic, 2.1. Chemistry invading as filamentous hyphae but proliferating as yeasts (Gale et al. 1998), whereas others like the molds, Asper- As described previously, we have applied the Self-Regen- gillus, are exclusively filamentous (Latge´ 2001). Fungi erating Stereocentre (SRS) approach (Seebach et al. 1996) like Aspergillus grow by tip growth and form basal cell- to the synthesis of (R)-homocitrate (Ma and Palmer 2000). like compartments by crosswall insertion (Hamer et al. This approach uses the steric hindrance of the tert-butyl 1999) creating multicellular colonies. Basal cells in these group of 4 to control the face of alkylation of the planar colonies are quiescent for growth but metabolically active, enolate intermediate. In this approach, the electrophile and reinitiate growth for normal branching or in response added was eventually modified to form the propionate to mechanical damage to the mycelium. This leads to a moiety of homocitrate, thus substitution of other electro- considerable difficulty in accurately estimating viability philes was an obvious extension of the technique, as illu- after anti-fungal treatments because tip growth assays do strated in Scheme 3. Because an equally large or larger not accurately reflect the number of potentially viable moiety was desired in this position, substituted methyl cells. A colorimetric assay to quantify fungal growth has ortho-, meta-, and para-(bromomethyl)benzoates were chosen as electrophiles. The presence of the electron-with- drawing methyl carboxylate substituent would be pre- CO2R CO2R CO2R dicted to result in a less reactive electrophile relative to H H H OH H OH benzyl bromide, and this was observed in our work. The RO2C OH RO2C H RO2C H para-substituted compound gave the desired product 5 in H H H H H H moderate yield (36%), about half that obtained when ben- zyl bromide was used (Seebach et al. 1984). The ortho- substituted compound gave the desired product in very CO2R low yield (ca. 1%), and reaction with the meta-substituted CO2R CO2R compound resulted in no product in our hands. As re- 1a:R=H 2a:R=H 3a:R=H ported by Seebach et al. (1984), high stereoselectivity was 1b:R=Me 2b:R=Me 3b:R=Me obtained; the presence of the undesired diastereomer could 94 Pharmazie 59 (2004) 2 ORIGINAL ARTICLES Scheme 3 OR O O O O O O H C OH i, ii H2C iii 2 O CO H CO2R H 36% 2 95% CO2H RO C MeO2C 2 45 1a:R=H iv 1b:R=Me i.) LiHMDS/THF, methyl para-(bromomethyl)benzoate, À78 C, 3 hr. ii.) 1 N HCl. iii) 50% aqueous TFA, rt, 6 hr. iv.) CH2N2 /DMF, 10 min Scheme 4 CO2Me CO2Me CO2H H OH i, ii H OH iii H OH CO Me CO H H H 35% H CH2 2 92% H CH2 2 CO2Me CO2Me CO2H 2b 2a i.) LDA/THF, methyl para-(bromomethyl)benzoate, À78 C, overnight.
Load more

Recommended publications
  • 12) United States Patent (10
    US007635572B2 (12) UnitedO States Patent (10) Patent No.: US 7,635,572 B2 Zhou et al. (45) Date of Patent: Dec. 22, 2009 (54) METHODS FOR CONDUCTING ASSAYS FOR 5,506,121 A 4/1996 Skerra et al. ENZYME ACTIVITY ON PROTEIN 5,510,270 A 4/1996 Fodor et al. MICROARRAYS 5,512,492 A 4/1996 Herron et al. 5,516,635 A 5/1996 Ekins et al. (75) Inventors: Fang X. Zhou, New Haven, CT (US); 5,532,128 A 7/1996 Eggers Barry Schweitzer, Cheshire, CT (US) 5,538,897 A 7/1996 Yates, III et al. s s 5,541,070 A 7/1996 Kauvar (73) Assignee: Life Technologies Corporation, .. S.E. al Carlsbad, CA (US) 5,585,069 A 12/1996 Zanzucchi et al. 5,585,639 A 12/1996 Dorsel et al. (*) Notice: Subject to any disclaimer, the term of this 5,593,838 A 1/1997 Zanzucchi et al. patent is extended or adjusted under 35 5,605,662 A 2f1997 Heller et al. U.S.C. 154(b) by 0 days. 5,620,850 A 4/1997 Bamdad et al. 5,624,711 A 4/1997 Sundberg et al. (21) Appl. No.: 10/865,431 5,627,369 A 5/1997 Vestal et al. 5,629,213 A 5/1997 Kornguth et al. (22) Filed: Jun. 9, 2004 (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2005/O118665 A1 Jun. 2, 2005 EP 596421 10, 1993 EP 0619321 12/1994 (51) Int. Cl. EP O664452 7, 1995 CI2O 1/50 (2006.01) EP O818467 1, 1998 (52) U.S.
    [Show full text]
  • A Prokaryotic Gene Cluster Involved in Synthesis of Lysine Through the Amino Adipate Pathway: a Key to the Evolution of Amino Acid Biosynthesis
    Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Research A Prokaryotic Gene Cluster Involved in Synthesis of Lysine through the Amino Adipate Pathway: A Key to the Evolution of Amino Acid Biosynthesis Hiromi Nishida,1 Makoto Nishiyama,2,4 Nobuyuki Kobashi,2 Takehide Kosuge,3 Takayuki Hoshino,3 and Hisakazu Yamane2 1Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; 2Biotechnology Research Center, The University of Tokyo, Tokyo 113-8657, Japan; 3Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan In previous studies we determined the nucleotide sequence of the gene cluster containing lys20, hacA (lys4A), hacB (lys4B), orfE, orfF, rimK, argC, and argB of Thermus thermophilus, an extremely thermophilic bacterium. In this study, we characterized the role of each gene in the cluster by gene disruption and examined auxotrophy in the disruptants. All disruptants except for the orfE disruption showed a lysine auxotrophic phenotype. This was surprising because this cluster consists of genes coding for unrelated proteins based on their names, which had been tentatively designated by homology analysis. Although the newly found pathway contains ␣-aminoadipic acid as a lysine biosynthetic intermediate, this pathway is not the same as the eukaryotic one. When each of the gene products was phylogenetically analyzed, we found that genes evolutionarily-related to the lysine biosynthetic genes in T. thermophilus were all present in a hyperthermophilic and anaerobic archaeon, Pyrococcus horikoshii, and formed a gene cluster in a manner similar to that in T. thermophilus. Furthermore, this gene cluster was analogous in part to the present leucine and arginine biosyntheses pathways.
    [Show full text]
  • Metabolic Engineering of Corynebacterium Glutamicum for Production of the Adipate
    Metabolic engineering of Corynebacterium glutamicum for production of the adipate precursor 2-oxoadipate A dissertation submitted to the Mathematisch-Naturwissenschaftliche Fakultät of the Heinrich-Heine-Universität Düsseldorf presented by Markus Sebastian Spelberg born in Krefeld October 2013 The thesis in hand has been performed at the Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, from September 2009 until October 2013 under the supervision of Prof. Dr. Michael Bott. Printed with the permission of the Mathematisch-Naturwissenschaftliche Fakultät of the Heinrich-Heine-Universität Düsseldorf Examiner: Prof. Dr. Michael Bott Institute of Bio- and Geosciences 1, IBG-1: Biotechnology Forschungszentrum Jülich GmbH Coexaminer: PD Dr. Ulrich Schulte Department of Biochemistry I Heinrich-Heine-Universität Düsseldorf th Date of the oral examination: 5 December 2013 Content CONTENT 1 Summary ............................................................................................................................ 1 1.1 Summary ...................................................................................................................... 1 1.2 Zusammenfassung ....................................................................................................... 3 2 Introduction ........................................................................................................................ 5 2.1 Significance and application of adipate ......................................................................
    [Show full text]
  • Figure1 Gabriel
    E u k a E Unikonts Ch A r x y r c ota chaeplastida r a omal va V t iridiplantae F e M un v s eola eta Di g k i z a t oa r es y a He R Hap C E Api Ciliophora Al P Neocallimastigo Amoeb F Basidio M Choan A St R A M Pla Nema Cnidaria Pla P Chlo Glau Cho ornicata uglen arabasalia o h hodop r s r ollusca ic r v yp th c r i ep t t c eolata za i c o e r yhelminthe f r oz t osporidia r omplexa e c r t r m data op opoda t op r okon op op r t op i oa o a oda a y o m o h z c h h h z h z h oa yta ota y oa yta yta yta yta oa yta c t ota op h s yta m y c ota ATP phosphoribosyltransferase H1 phosphoribosyl-ATP pyrophosphohydrolase H2 Phosphoribosyl-AMP cyclohydrolase H3 5-proFAR isomerase H4 H Glutamine amidotransferase H5 Imidazoleglycerol-phosphate dehydratase H6 Histidinol-phosphate aminotransferase H7 Histidinol phosphatase H8 Histidinol dehydrogenase H9 3-deoxy-7-phosphoheptulonate synthase FW1 3-dehydroquinate synthase FW2 3-dehydroquinate dehydratase FW3 Shikimate 5-dehydrogenase FW4 Shikimate kinase FW5 F 3-phosphoshikimate 1-carboxyvinyltransferase FW6 Chorismate synthase FW7 Chorismate mutase F8 Prephenate dehydratase F9 4 distinct aminotransferases F10 3-deoxy-7-phosphoheptulonate synthase FW1 3-dehydroquinate synthase FW2 3-dehydroquinate dehydratase FW3 Shikimate 5-dehydrogenase FW4 Shikimate kinase FW5 3-phosphoshikimate 1-carboxyvinyltransferase FW6 W Chorismate synthase FW7 Anthranilate synthase W8 Anthranilate phosphoribosyltransferase W9 N(5`-phosphoribosyl) anthranilate isomerase W10 Indole-3-glycerol phosphate synthase W11 Tryptophan
    [Show full text]
  • POLSKIE TOWARZYSTWO BIOCHEMICZNE Postępy Biochemii
    POLSKIE TOWARZYSTWO BIOCHEMICZNE Postępy Biochemii http://rcin.org.pl WSKAZÓWKI DLA AUTORÓW Kwartalnik „Postępy Biochemii” publikuje artykuły monograficzne omawiające wąskie tematy, oraz artykuły przeglądowe referujące szersze zagadnienia z biochemii i nauk pokrewnych. Artykuły pierwszego typu winny w sposób syntetyczny omawiać wybrany temat na podstawie możliwie pełnego piśmiennictwa z kilku ostatnich lat, a artykuły drugiego typu na podstawie piśmiennictwa z ostatnich dwu lat. Objętość takich artykułów nie powinna przekraczać 25 stron maszynopisu (nie licząc ilustracji i piśmiennictwa). Kwartalnik publikuje także artykuły typu minireviews, do 10 stron maszynopisu, z dziedziny zainteresowań autora, opracowane na podstawie najnow­ szego piśmiennictwa, wystarczającego dla zilustrowania problemu. Ponadto kwartalnik publikuje krótkie noty, do 5 stron maszynopisu, informujące o nowych, interesujących osiągnięciach biochemii i nauk pokrewnych, oraz noty przybliżające historię badań w zakresie różnych dziedzin biochemii. Przekazanie artykułu do Redakcji jest równoznaczne z oświadczeniem, że nadesłana praca nie była i nie będzie publikowana w innym czasopiśmie, jeżeli zostanie ogłoszona w „Postępach Biochemii”. Autorzy artykułu odpowiadają za prawidłowość i ścisłość podanych informacji. Autorów obowiązuje korekta autorska. Koszty zmian tekstu w korekcie (poza poprawieniem błędów drukarskich) ponoszą autorzy. Artykuły honoruje się według obowiązujących stawek. Autorzy otrzymują bezpłatnie 25 odbitek swego artykułu; zamówienia na dodatkowe odbitki (płatne) należy zgłosić pisemnie odsyłając pracę po korekcie autorskiej. Redakcja prosi autorów o przestrzeganie następujących wskazówek: Forma maszynopisu: maszynopis pracy i wszelkie załączniki należy nadsyłać w dwu egzem­ plarzach. Maszynopis powinien być napisany jednostronnie, z podwójną interlinią, z marginesem ok. 4 cm po lewej i ok. 1 cm po prawej stronie; nie może zawierać więcej niż 60 znaków w jednym wierszu nie więcej niż 30 wierszy na stronie zgodnie z Normą Polską.
    [Show full text]
  • Physiological Models of Geobacter Sulfurreducens and Desulfobacter Postgatei to Understand Uranium Remediation in Subsurface Systems
    University of Massachusetts Amherst ScholarWorks@UMass Amherst Doctoral Dissertations Dissertations and Theses November 2014 PHYSIOLOGICAL MODELS OF GEOBACTER SULFURREDUCENS AND DESULFOBACTER POSTGATEI TO UNDERSTAND URANIUM REMEDIATION IN SUBSURFACE SYSTEMS Roberto Orellana University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/dissertations_2 Part of the Environmental Microbiology and Microbial Ecology Commons, and the Microbial Physiology Commons Recommended Citation Orellana, Roberto, "PHYSIOLOGICAL MODELS OF GEOBACTER SULFURREDUCENS AND DESULFOBACTER POSTGATEI TO UNDERSTAND URANIUM REMEDIATION IN SUBSURFACE SYSTEMS" (2014). Doctoral Dissertations. 278. https://doi.org/10.7275/5822237.0 https://scholarworks.umass.edu/dissertations_2/278 This Open Access Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks@UMass Amherst. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. PHYSIOLOGICAL MODELS OF GEOBACTER SULFURREDUCENS AND DESULFOBACTER POSTGATEI TO UNDERSTAND URANIUM REMEDIATION IN SUBSURFACE SYSTEMS A Dissertation Presented by ROBERTO ORELLANA ROMAN Submitted to the Graduate School of the University of Massachusetts Amherst in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY September 2014 Microbiology Department © Copyright by Roberto Orellana Roman 2014 All Rights
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2012/0266329 A1 Mathur Et Al
    US 2012026.6329A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0266329 A1 Mathur et al. (43) Pub. Date: Oct. 18, 2012 (54) NUCLEICACIDS AND PROTEINS AND CI2N 9/10 (2006.01) METHODS FOR MAKING AND USING THEMI CI2N 9/24 (2006.01) CI2N 9/02 (2006.01) (75) Inventors: Eric J. Mathur, Carlsbad, CA CI2N 9/06 (2006.01) (US); Cathy Chang, San Marcos, CI2P 2L/02 (2006.01) CA (US) CI2O I/04 (2006.01) CI2N 9/96 (2006.01) (73) Assignee: BP Corporation North America CI2N 5/82 (2006.01) Inc., Houston, TX (US) CI2N 15/53 (2006.01) CI2N IS/54 (2006.01) CI2N 15/57 2006.O1 (22) Filed: Feb. 20, 2012 CI2N IS/60 308: Related U.S. Application Data EN f :08: (62) Division of application No. 1 1/817,403, filed on May AOIH 5/00 (2006.01) 7, 2008, now Pat. No. 8,119,385, filed as application AOIH 5/10 (2006.01) No. PCT/US2006/007642 on Mar. 3, 2006. C07K I4/00 (2006.01) CI2N IS/II (2006.01) (60) Provisional application No. 60/658,984, filed on Mar. AOIH I/06 (2006.01) 4, 2005. CI2N 15/63 (2006.01) Publication Classification (52) U.S. Cl. ................... 800/293; 435/320.1; 435/252.3: 435/325; 435/254.11: 435/254.2:435/348; (51) Int. Cl. 435/419; 435/195; 435/196; 435/198: 435/233; CI2N 15/52 (2006.01) 435/201:435/232; 435/208; 435/227; 435/193; CI2N 15/85 (2006.01) 435/200; 435/189: 435/191: 435/69.1; 435/34; CI2N 5/86 (2006.01) 435/188:536/23.2; 435/468; 800/298; 800/320; CI2N 15/867 (2006.01) 800/317.2: 800/317.4: 800/320.3: 800/306; CI2N 5/864 (2006.01) 800/312 800/320.2: 800/317.3; 800/322; CI2N 5/8 (2006.01) 800/320.1; 530/350, 536/23.1: 800/278; 800/294 CI2N I/2 (2006.01) CI2N 5/10 (2006.01) (57) ABSTRACT CI2N L/15 (2006.01) CI2N I/19 (2006.01) The invention provides polypeptides, including enzymes, CI2N 9/14 (2006.01) structural proteins and binding proteins, polynucleotides CI2N 9/16 (2006.01) encoding these polypeptides, and methods of making and CI2N 9/20 (2006.01) using these polynucleotides and polypeptides.
    [Show full text]
  • All Enzymes in BRENDA™ the Comprehensive Enzyme Information System
    All enzymes in BRENDA™ The Comprehensive Enzyme Information System http://www.brenda-enzymes.org/index.php4?page=information/all_enzymes.php4 1.1.1.1 alcohol dehydrogenase 1.1.1.B1 D-arabitol-phosphate dehydrogenase 1.1.1.2 alcohol dehydrogenase (NADP+) 1.1.1.B3 (S)-specific secondary alcohol dehydrogenase 1.1.1.3 homoserine dehydrogenase 1.1.1.B4 (R)-specific secondary alcohol dehydrogenase 1.1.1.4 (R,R)-butanediol dehydrogenase 1.1.1.5 acetoin dehydrogenase 1.1.1.B5 NADP-retinol dehydrogenase 1.1.1.6 glycerol dehydrogenase 1.1.1.7 propanediol-phosphate dehydrogenase 1.1.1.8 glycerol-3-phosphate dehydrogenase (NAD+) 1.1.1.9 D-xylulose reductase 1.1.1.10 L-xylulose reductase 1.1.1.11 D-arabinitol 4-dehydrogenase 1.1.1.12 L-arabinitol 4-dehydrogenase 1.1.1.13 L-arabinitol 2-dehydrogenase 1.1.1.14 L-iditol 2-dehydrogenase 1.1.1.15 D-iditol 2-dehydrogenase 1.1.1.16 galactitol 2-dehydrogenase 1.1.1.17 mannitol-1-phosphate 5-dehydrogenase 1.1.1.18 inositol 2-dehydrogenase 1.1.1.19 glucuronate reductase 1.1.1.20 glucuronolactone reductase 1.1.1.21 aldehyde reductase 1.1.1.22 UDP-glucose 6-dehydrogenase 1.1.1.23 histidinol dehydrogenase 1.1.1.24 quinate dehydrogenase 1.1.1.25 shikimate dehydrogenase 1.1.1.26 glyoxylate reductase 1.1.1.27 L-lactate dehydrogenase 1.1.1.28 D-lactate dehydrogenase 1.1.1.29 glycerate dehydrogenase 1.1.1.30 3-hydroxybutyrate dehydrogenase 1.1.1.31 3-hydroxyisobutyrate dehydrogenase 1.1.1.32 mevaldate reductase 1.1.1.33 mevaldate reductase (NADPH) 1.1.1.34 hydroxymethylglutaryl-CoA reductase (NADPH) 1.1.1.35 3-hydroxyacyl-CoA
    [Show full text]
  • KO Id Functional Hierarchy 1 Functional Hierarchy 2 Module Id Module Description Name Definition Life Style K00611 Amino Acid Me
    KO_id Functional hierarchy 1 Functional hierarchy 2 Module_id Module description Name Definition Life_style K00611 Amino acid metabolism Arginine and proline metabolism M00029 Urea cycle [PATH:map00220 map01230 map01100] OTC, argF, argI ornithine carbamoyltransferase [EC:2.1.3.3] FL-ls K00611 Amino acid metabolism Arginine and proline metabolism M00844 Arginine biosynthesis, ornithine => arginine [PATH:map00220OTC, map01230argF, argI map01100]ornithine carbamoyltransferase [EC:2.1.3.3] FL-ls K00286 Amino acid metabolism Arginine and proline metabolism M00015 Proline biosynthesis, glutamate => proline [PATH:map00330proC map01230 map01100]pyrroline-5-carboxylate reductase [EC:1.5.1.2] PA-ls K00818 Amino acid metabolism Arginine and proline metabolism M00028 Ornithine biosynthesis, glutamate => ornithine [PATH:map00220E2.6.1.11, map01210 argD map01230acetylornithine map01100] aminotransferase [EC:2.6.1.11] PA-ls K00619 Amino acid metabolism Arginine and proline metabolism M00028 Ornithine biosynthesis, glutamate => ornithine [PATH:map00220argA map01210 map01230amino-acid map01100] N-acetyltransferase [EC:2.3.1.1] PA-ls K00620 Amino acid metabolism Arginine and proline metabolism M00028 Ornithine biosynthesis, glutamate => ornithine [PATH:map00220argJ map01210 map01230glutamate map01100] N-acetyltransferase / amino-acid N-acetyltransferasePA-ls [EC:2.3.1.35 2.3.1.1] K00930 Amino acid metabolism Arginine and proline metabolism M00028 Ornithine biosynthesis, glutamate => ornithine [PATH:map00220argB map01210 map01230acetylglutamate map01100]
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0240226A1 Mathur Et Al
    US 20150240226A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0240226A1 Mathur et al. (43) Pub. Date: Aug. 27, 2015 (54) NUCLEICACIDS AND PROTEINS AND CI2N 9/16 (2006.01) METHODS FOR MAKING AND USING THEMI CI2N 9/02 (2006.01) CI2N 9/78 (2006.01) (71) Applicant: BP Corporation North America Inc., CI2N 9/12 (2006.01) Naperville, IL (US) CI2N 9/24 (2006.01) CI2O 1/02 (2006.01) (72) Inventors: Eric J. Mathur, San Diego, CA (US); CI2N 9/42 (2006.01) Cathy Chang, San Marcos, CA (US) (52) U.S. Cl. CPC. CI2N 9/88 (2013.01); C12O 1/02 (2013.01); (21) Appl. No.: 14/630,006 CI2O I/04 (2013.01): CI2N 9/80 (2013.01); CI2N 9/241.1 (2013.01); C12N 9/0065 (22) Filed: Feb. 24, 2015 (2013.01); C12N 9/2437 (2013.01); C12N 9/14 Related U.S. Application Data (2013.01); C12N 9/16 (2013.01); C12N 9/0061 (2013.01); C12N 9/78 (2013.01); C12N 9/0071 (62) Division of application No. 13/400,365, filed on Feb. (2013.01); C12N 9/1241 (2013.01): CI2N 20, 2012, now Pat. No. 8,962,800, which is a division 9/2482 (2013.01); C07K 2/00 (2013.01); C12Y of application No. 1 1/817,403, filed on May 7, 2008, 305/01004 (2013.01); C12Y 1 1 1/01016 now Pat. No. 8,119,385, filed as application No. PCT/ (2013.01); C12Y302/01004 (2013.01); C12Y US2006/007642 on Mar. 3, 2006.
    [Show full text]
  • A Dissertation Entitled Development of Selective Inhibitors Against
    A Dissertation entitled Development of Selective Inhibitors against Enzymes Involved in the Aspartate Biosynthetic Pathway for Antifungal Drug Development By Gopal P. Dahal Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry ________________________________________ Dr. Ronald E. Viola, Committee Chair ________________________________________ Dr. Donald Ronning, Committee Member ________________________________________ Dr. Jianglong Zhu, Committee Member ________________________________________ Dr. Viranga Tillekeratne, Committee Member ________________________________________ Dr. Amanda C. Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August 2018 © Copyright by Gopal P. Dahal, 2018 This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Development of Selective Inhibitors against Enzymes Involved in the Aspartate Biosynthetic Pathway for Antifungal Drug Development by Gopal P. Dahal Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry The University of Toledo August 2018 Aspartate semialdehyde dehydrogenase (ASADH) functions at a critical junction in the aspartate biosynthetic pathway and represents a validated target for antimicrobial drug design. This enzyme catalyzes the NADPH-dependent reductive dephosphorylation of β-aspartyl phosphate to produce the key intermediate aspartate semialdehyde. Production of this intermediate represents the first committed step for the biosynthesis of several essential amino acids in fungi and in bacteria. The absence of this enzyme in humans and other mammals will allow the selective targeting of any ASADH inhibitors against pathogenic microorganisms. We have accumulated significant structural and mechanistic information about the bacterial ASADHs, but have only limited knowledge of their fungal counterparts.
    [Show full text]
  • Supplementary Material (ESI) for Natural Product Reports
    Electronic Supplementary Material (ESI) for Natural Product Reports. This journal is © The Royal Society of Chemistry 2014 Supplement to the paper of Alexey A. Lagunin, Rajesh K. Goel, Dinesh Y. Gawande, Priynka Pahwa, Tatyana A. Gloriozova, Alexander V. Dmitriev, Sergey M. Ivanov, Anastassia V. Rudik, Varvara I. Konova, Pavel V. Pogodin, Dmitry S. Druzhilovsky and Vladimir V. Poroikov “Chemo- and bioinformatics resources for in silico drug discovery from medicinal plants beyond their traditional use: a critical review” Contents PASS (Prediction of Activity Spectra for Substances) Approach S-1 Table S1. The lists of 122 known therapeutic effects for 50 analyzed medicinal plants with accuracy of PASS prediction calculated by a leave-one-out cross-validation procedure during the training and number of active compounds in PASS training set S-6 Table S2. The lists of 3,345 mechanisms of action that were predicted by PASS and were used in this study with accuracy of PASS prediction calculated by a leave-one-out cross-validation procedure during the training and number of active compounds in PASS training set S-9 Table S3. Comparison of direct PASS prediction results of known effects for phytoconstituents of 50 TIM plants with prediction of known effects through “mechanism-effect” and “target-pathway- effect” relationships from PharmaExpert S-79 S-1 PASS (Prediction of Activity Spectra for Substances) Approach PASS provides simultaneous predictions of many types of biological activity (activity spectrum) based on the structure of drug-like compounds. The approach used in PASS is based on the suggestion that biological activity of any drug-like compound is a function of its structure.
    [Show full text]