Amino acid synthesis pathway in fungi -
From this point of view, the fungi-specific pathways of methionine and tryptophan biosynthesis seem the most promising targets, since the serum levels of these two human-essential amino acids are especially low Tagliamonte et al.
Another challenge is a successful delivery of effective enzyme inhibitors into fugal cells, since inhibitors of enzymes of amino acid biosynthesis are often hydrophilic molecules, unable to cross the cytoplasmic membrane barrier.
This problem may be solved by application of the portage transport approach Hwang et al. Examples of successful application of both approaches have been already reported Aoki et al.
Some reports cited in this review indicate also a possibility of good therapeutic effect of existing antifungal drugs in combination with inhibitors of amino acid biosynthesis Kingsbury and McCusker a , b. Summing up, the search for antifungal drug candidates targeting enzymes of amino acid biosynthesis is undoubtedly worth sustaining.
Diagram summarizing the most promising antifungal molecular targets in amino acids biosynthesis pathways. Abdo MR, Joseph P, Mortier J et al Anti-virulence strategy against Brucella suis : synthesis, biological evaluation and molecular modeling of selective histidinol dehydrogenase inhibitors.
Org Biomol Chem — CAS PubMed Google Scholar. Adachi K, Covington A, Darveaux B et al Methods for the identification of inhibitors of pyrrolinecarboxylate reductase as antibiotics.
Patent USA A1. Clin Microbiol Rev — CAS PubMed Central PubMed Google Scholar. Aoki Y, Kongoh M, Nakamura M et al A new methionine antagonist that has antifungal activity: mode of action.
Jpn J Antibiot — Google Scholar. Aoki Y, Kamiyama T, Fujii T et al Design of an antifungal methionine inhibitor not antagonized by methionine.
Biol Pharm Bull — Aoki Y, Yamamoto M, Hosseini-Mazinani SM et al Antifungal azoxybacilin exhibits activity by inhibiting gene expression of sulfite reductase. Antimicrob Agents Chemother — Aral B, Kamoun P The proline biosynthesis in living organisms.
Amino Acids — CAS Google Scholar. Arevalo-Rodrigurez M, Xuewen P, Boeke JD, Heitman J FKBP12 controls aspartate pathway flux in saccharomyces cerevisiae to prevent toxic intermediate accumulation. Eucaryotic Cell — Baldwin B, Brownell K, Rees S et al The mode of action of the anilide fungicide SC Chem p Balhadère PV, Foster AJ, Talbot NJ Identification of pathogenicity mutants of the rice blast fungus Magnaporthe grisea by insertional mutagenesis.
Am Phytopathol Soc — Banerjee RV, Matthews RG Cobalamin-dependent methionine synthase. FASEB J — Banerjee D, Burkard L, Panepinto JC Inhibition of nucleotide biosynthesis potentiates the antifungal activity of amphotericin B. PLoS One 9:e PubMed Central PubMed Google Scholar.
Bareich DC, Nazi I, Wright G Simultaneous in vitro assay of the first four enzymes in the fungal aspartate pathway identifies a new class of aspartate kinase inhibitor.
Chem Biol — Becker J, Kauffman S, Hauser M et al Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model.
Proc Natl Acad Sci USA — Beckmann N, Schafferer L, Schrettl M et al Characterization of the link between ornithine, arginine, polyamine and siderophore metabolism in Aspergillus fumigatus. PLoS One 8:e Bhattacharjee J α-Aminoadipate pathway for the biosynthesis of lysine in lower eukaryotes.
Crit Rev Microbiol — Birrell G, Giaever G, Chu A et al A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity. Birrell G, Brown J, Wu H et al Transcriptional response of Saccharomyces cerevisiae to DNA-damaging agents does not identify the genes that protect against these agents.
Boguslawski G, Stetler D Aspects of physiology of Histoplasma capsulatum. Mycopathologia — Borisova SA, Circello BT, Zhang JK et al Biosynthesis of rhizocticins, antifungal phosphonate oligopeptides produced by Bacillus subtilis ATC Braus G Aromatic amino acid biosynthesis in the yeast Saccharomyces cerevisiae : a model system for the regulation of a eukaryotic biosynthetic pathway.
Microbiol Mol Biol Rev — Brown G, Bamford A, Bowyer J et al Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorganic Med Chem Lett — Brunke S, Seider K, Almeida RS et al Candida glabrata tryptophan-based pigment production via the Ehrlich pathway. Mol Microbiol — Choudhury R, Punekar NS Competitive inhibition of glutamate dehydrogenase reaction.
FEBS Lett — Choudhury R, Noor S, Varadarajalu LP, Punekar NS Delineation of an in vivo inhibitor for Aspergillus glutamate dehydrogenase. Enzyme Microb Technol — Cunin R, Glansdorff N, Piérard A, Stalon V Biosynthesis and metabolism of arginine in bacteria. Microbiol Rev — De Pascale G, Griffiths EJ, Shakya T et al Identification and characterization of new inhibitors of fungal homoserine kinase.
ChemBioChem — PubMed Google Scholar. Duggleby R, Pang S, Yu H, Guddat LW Systematic characterization of mutations in yeast acetohydroxyacid synthase. Interpretation of herbicide-resistance data. Eur J Biochem — Ejim L, Mirza IA, Capone C et al a New phenolic inhibitors of yeast homoserine dehydrogenase.
Bioorg Med Chem — Ejim LJ, Costa VMD, Elowe NH et al b Cystathionine beta-lyase is important for virulence of Salmonella enterica serovar typhimurium. Infect Immun — Ejim LJ, Blanchard JE, Koteva KP et al Inhibitors of bacterial cystathionine beta-lyase: leads for new antimicrobial agents and probes of enzyme structure and function.
J Med Chem — Fasman G Handbook of biochemistry and molecular biology, third. CRC Pess, Cleveland. Forlani G, Petrollino D, Fusetti M et al Δ1-Pyrrolinecarboxylate reductase as a new target for therapeutics: inhibition of the enzyme from Streptococcus pyogenes and effects in vivo.
Formica JV, Regelson W Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol — Fritz R, Lanen C, Chapeland-Leclerc F, Leroux P Effect of the anilinopyrimidine fungicide pyrimethanil on the cystathionine β-lyase of Botrytis cinerea. Pestic Biochem Physiol — Fu J, Wu J, Jiang J et al Cystathionine γ-synthase is essential for methionine biosynthesis in Fusarium graminearum.
Fungal Biol — Fujita Y, Ukena E, Iefuji H et al Homocysteine accumulation causes a defect in purine biosynthesis: further characterization of Schizosaccharomyces pombe methionine auxotrophs.
Microbiology — Fujiu M, Sawairi S, Shimada H et al Azoxybacilin, a novel antifungal agent produced by Bacillus cereus NR Production, isolation and structure elucidation. Gabriel I, Vetter ND, Palmer DRJ et al Homoisocitrate dehydrogenase from Candida albicans : properties, inhibition, and targeting by an antifungal pro-drug.
FEMS Yeast Res — Gahungu M, Arguelles-Arias A, Fickers P et al Synthesis and biological evaluation of potential threonine synthase inhibitors: Rhizocticin A and Plumbemycin A. Gibbons GF, Howard DH Arginine auxotrophs of Candida albicans deficient in argininosuccinate lyase.
J Gen Microbiol — González JC, Banerjee RV, Huang S et al Comparison of cobalamin-independent and cobalamin-dependent methionine synthases from Escherichia coli : two solutions to the same chemical problem.
Biochemistry — Gophna U, Bapteste E, Doolittle FW et al Evolutionary plasticity of methionine biosynthesis. Gene — Grandoni JA, Marta PT, Schloss JV Inhibitors of branched-chain amino acid biosynthesis as potential antituberculosis agents.
J Antimicrob Chemother — Gray S, Bhattacharjee J Biosynthesis of lysine in Saccharomyces cerevisiae : regulation of homoisocitrate synthase in analogue-resistant mutants. Gustavsson M, Ronne H Evidence that tRNA modifying enzymes are important in vivo targets for 5-fluorouracil in yeast.
RNA — Hamer L, Adachi K, Dezwaan T et al Methods for the identification of inhibitors of 3-isopropylmalate dehydratase as antibiotics.
Patent USA Han Y-K, Lee T, Han K-H et al Functional analysis of the homoserine O-acetyltransferase gene and its identification as a selectable marker in Gibberella zeae. Curr Genet — Hatanaka H, Ariga N, Nagai J, Katsuki H Accumulation of a sterol intermediate during reaction in the presence of homocysteine with cell-free extract of yeast.
Biochem Biophys Res Commun — Hoskins J, Butler J Evidence for distinct DNA- and RNA-based mechanisms of 5-fluorouracil cytotoxicity in Saccharomyces cerevisiae.
Yeast — Hudson R, Daniel R L-Glutamate dehydrogenases: distribution, properties and mechanism. Comp Biochem Physiol — Mol Plant Microbe Interact — Hwang SY, Berges DA, Taggart JJ, Gilvarg C Portage transport of sulfanilamide and sulfanilic acid.
Jacques S, Mirza A, Ejim L et al Enzyme-assisted suicide: molecular basis for the antifungal activity of 5-hydroxyoxonorvaline by potent inhibition of homoserine dehydrogenase. Jakubowski H Proofreading in vivo: editing of homocysteine by methionyl-tRNA synthetase in Escherichia coli.
Jakubowski H The determination of homocysteine-thiolactone in biological samples. Anal Biochem — Jakubowski H Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci — Jones E, Fink G Regulation of amino acid and nucleotide biosynthesis.
In: Strathern J, Jones E eds Mol. Yeast Saccharomyces Metab. Gene Expr. Cold Spring Harbor Laboratory, New York, pp — Joshi CV, Pathan EK, Punekar NS et al A biochemical correlate of dimorphism in a zygomycete Benjaminiella poitrasii : characterization of purified NAD-dependent glutamate dehydrogenase, a target for antifungal agents.
Antonie Van Leeuwenhoek — Kacprzak MM, Lewandowska I, Matthews RG, Paszewski A Transcriptional regulation of methionine synthase by homocysteine and choline in Aspergillus nidulans. Biochem J — Kim HS, Fay JC Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds.
Kingsbury JM Cryptococcus neoformans Ilv2p confers resistance to sulfometuron methyl and is required for survival at 37 C and in vivo. Kingsbury JM, McCusker JH Threonine biosynthetic genes are essential in Cryptococcus neoformans.
Eukaryot Cell — Kingsbury JM, Goldstein AL, Mccusker JH Role of nitrogen and carbon transport, regulation, and metabolism genes for Saccharomyces cerevisiae survival in vivo. Eucaryotic cell — Kishore GM, Shah DM Amino acid biosynthesis inhibitors as herbicides. Annu Rev Biochem — Kohlhaw GB Leucine biosynthesis in fungi: entering metabolism through the back door.
Krämer H-J, Podobinska M, Bartsch A et al Malassezin, a novel agonist of the aryl hydrocarbon receptor from the yeast Malassezia furfur , induces apoptosis in primary human melanocytes. Kugler M, Loeffier W, Rapp C et al Rhizocticin A, an antifungal phosphono-oligopeptide of Bacillus subtilis ATC biological proporties.
Arch Microbiol — Kur K, Gabriel I, Morschhäuser J et al Disruption of homocitrate synthase genes in Candida albicans affects growth but not virulence. Kwon-Chung K, Rhodes JC Encapsulation and melanin formation as indicators of virulence in Cryptococcus neoformans.
Kwon-Chung K, Polacheck I, Popkin T Melanin lacking mutants of Cryptococcus neoformans and their virulence for mice. J Bacteriol — Laber B, Lindell S, Pohlenz H Inactivation of Escherichia coli threonine synthase by DL-Zaminophosphonopentenoic acid.
Lee Y-T, Cui C-J, Chow EWL et al Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase. Leroux P Recent developments in the mode of action of fungicides. Pest Manag Sci — Leroux P, Fritz R, Debieu D et al Mechanisms of resistance to fungicides in field strains of Botrytis cinerea.
Lewis A, Waterhouse C, Jacobs R Whole-blood an plasma amino acid analysis: gas-liquid and cation-exchange chromatography compared. Clin Chem — Liebmann B, Muhleisen T, Muller M et al Deletion of the Aspergillus fumigatus lysine biosynthesis gene lysF encoding homoaconitase leads to attenuated virulence in a low-dose mouse infection model of invasive aspergillosis.
Liu X-H, Shi Y-X, Ma Y et al Synthesis, antifungal activities and 3D-QSAR study of N- 5-substituted-1,3,4-thiadiazolyl cyclopropanecarboxamides.
Eur J Med Chem — Lo S, Hamer L, Hamer JE Molecular characterization of a cystathionine β-synthase gene, CBS1 in Magnaporthe grisea. Lo S, Montenegro-chamorro MV, Frank S et al Methods for the identification of inhibitors of asparagine synthase as antibiotics.
Patent USA B2. J Biol Chem — Maresca B, Kobayashi G Dimorphism in Histoplasma capsulatum : a model for the study of cell differentiation in pathogenic fungi. Matsumoto H, Nagao J, Cho T, Kodama J Evaluation of pathogenicity of Candida albicans in germination-ready states using a silkworm infection model.
Jpn J Med Mycol — McCammon M, Parks L Inhibition of sterol transmethylation by S-adenosylhomocysteine analogs. Medoff G, Painter A, Kobayashi G Mycelial- to yeast phase transitions of the dimorphic fungi Blastomyces dermatitidis and Paracoccidioides brasiliensis.
Milewska M, Prokop M, Gabriel I et al Antifungal activity of homoaconitate and homoisocitrate analogs. Molecules — Milewski S, Mignini F, Prasad R, Borowski E Unusual susceptibility of a multidrug-resistant yeast strain to peptidic antifungals unusual susceptibility of a multidrug-resistant yeast strain to peptidic antifungals.
Morya VK, Kumari S, Kim E Imperative pathway analysis to identify the potential drug target for Aspergillus infection. Morya VK, Kumari S, Kim E-K Virtual screening and evaluation of ketol-acid reducto-isomerase KARI as a putative drug target for Aspergillosis. Clin Proteomics — Motil K, Opekun A, Montandon C et al Leucine oxidation changes rapidly after dietary protein intake is altered in adult women but lysine flux is unchanged as is lysine incorporation into VLDL-apolipoprotein B J Nutr — Namiki F, Matsunaga M, Okuda M et al Mutation of an arginine biosynthesis gene causes reduced pathogenicity in Fusarium oxysporum f.
Nazi I, Scott A, Sham A et al Role of homoserine transacetylase as a new target for antifungal agents. Negredo A, Monteoliva L, Gil C et al Cloning, analysis and one-step disruption of the ARG5,6 gene of Candida albicans. Noor S, Punekar N Allosteric NADP-glutamate dehydrogenase from Aspergilli : purification, characterization and implications for metabolic regulation at the carbon—nitrogen interface.
PLoS One 7:e Pahwa S, Kaur S, Jain R, Roy N Structure based design of novel inhibitors for histidinol dehydrogenase from Geotrichum candidum. Bioorg Med Chem Lett — Palmer DRJ, Balogh H, Ma G et al Synthesis and antifungal properties of compounds which target the α-aminoadipate pathway. Pharmazie — Parks L, Casey W Physiological implications of sterol biosynthesis in yeast.
Annu Rev Microbiol — Pascon RC, Ganous TM, Kingsbury JM et al Cryptococcus neoformans methionine synthase: expression analysis and requirement for virulence. Paszewski A, Brzywczy J, Natorff R Sulphur metabolism. Prog Ind Microbiol — Peters J, Sypherd P Morphology-associated expression nicotinamide adenine dinucleotide-dependent glutamate dehydrogenase in Mucor racemosus.
Piotrowska M, Paszewski A Propargylglycine as a fungal inhibitor: effect on sulphur amino acid metabolism. Prasannan P, Suliman HS, Robertus JD Kinetic analysis of site-directed mutants of methionine synthase from Candida albicans.
Ravanel S, Gakière B, Job D, Douce R The specific features of methionine biosynthesis and metabolism in plants. BMC Res Notes — Rhodes JC, Howard DH Isolation and characterization of arginine auxotrophs of Cryptococcus neoformans. Rhodes JC, Polacheck I, Kwon-Chung K Phenoloxidase activity and virulence in isogenic strains of Cryptococcus neoformans.
Richie DL, Thompson KV, Studer C et al Identification and evaluation of novel acetolactate synthase inhibitors as antifungal agents. Rivalta I, Sultan MM, Lee N et al Allosteric pathways in imidazole glycerol phosphate synthase.
PNAS — Rogers K, Boots M, Boots S Molecular interaction of six aromatic competitive inhibitors with bovine liver glutamate dehydrogenase. Biochim Biophys Acta — Schöbel F, Jacobsen ID, Brock M Evaluation of lysine biosynthesis as an antifungal drug target: biochemical characterization of Aspergillus fumigatus homocitrate synthase and virulence studies.
Seong K, Hou Z, Tracy M et al Random insertional mutagenesis identifies genes associated with virulence in the wheat scab fungus Fusarium graminearum. Phytopathology — Serlupi-Crescenzi O, Kurtz MB, Champe SP Developmental defects resulting from arginine auxotrophy in Aspergillus nidulans.
Shepherd MG Pathogenicity of morphological and auxotrophic mutants of Candida albicans in experimental infections. Sieńko M, Paszewski A The metG gene of Aspergillus nidulans encoding cystathionine β-lyase: cloning and analysis. Sierotzki H, Wullschleger J, Alt M et al Potential mode of resistance to anilinopyrimidine fungicides in Botrytis cinerea.
In: Dehne H, Gisi U, Kuck K et al eds Mod. pp — Sousa S, McLaughlin M, Pereira S et al The ARO4 gene of Candida albicans encodes a tyrosine-sensitive DAHP synthase: evolution, functional conservation and phenotype of Aro3p- Aro4p-deficient mutants.
Suliman HS, Sawyer GM, Appling DR, Robertus JD Purification and properties of cobalamin-independent methionine synthase from Candida albicans and Saccharomyces cerevisiae. Arch Biochem Biophys — Suliman HS, Appling DR, Robertus JD The gene for cobalamin-independent methionine synthase is essential in Candida albicans : a potential antifungal target.
Tagliamonte A, Biggio G, Vargiu L, Gessa G Free tryptophan in serum controls brain tryptophan level and serotonin synthesis.
Life Sci — Tang CM, Smith JM, Arst HN, Holden DW Virulence studies of Aspergillus nidulans mutants requiring lysine or p-aminobenzoic acid in invasive pulmonary aspergillosis. Umbarger HE Amino acid biosynthesis and its regulation.
Whittington-Smith R, Baldwin B, Grindle M, Kelly S A molecular genetics approach to understanding the mode of action of a novel anilide fungicide.
p Yamaguchi H, Uchida K, Hiratani T et al RI, a new antifungal antibiotic. Ann N Y Acad Sci — Yamaki H, Yamaguchi M, Imamura H et al The mechanism of antifungal action of S aminooxohydroxypentanoic acid, RI the inhibition of homoserine dehydrogenase in Saccharomyces cerevisiae.
Yamamoto T, Eguchi T Thiahomoisocitrate: a highly potent inhibitor of homoisocitrate dehydrogenase involved in the α-aminoadipate pathway. Bioorganic Med Chem — Yamamoto T, Miyazaki K, Eguchi T Substrate specificity analysis and inhibitor design of homoisocitrate dehydrogenase.
Yang Z, Pascon RC, Alspaugh JA et al Molecular and genetic analysis of the Cryptococcus neoformans MET3 gene and met3 mutant. Yeates C Icofungipen PLIVA. Curr Opin Investig Drugs — Zabriskie TM, Jackson MD Lysine biosynthesis and metabolism in fungi.
Nat Prod Rep — Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Iwona Gabriel. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited.
Reprints and permissions. Jastrzębowska, K. Inhibitors of amino acids biosynthesis as antifungal agents. Amino Acids 47 , — Download citation. Received : 02 June Accepted : 05 November Published : 20 November Issue Date : February Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.
Download PDF. Abstract Fungal microorganisms, including the human pathogenic yeast and filamentous fungi, are able to synthesize all proteinogenic amino acids, including nine that are essential for humans. Molecular targets for antifungals in amino acid and protein biosynthetic pathways Article Open access 03 June Peptaibols as Potential Antifungal and Anticancer Antibiotics: Current and Foreseeable Development Review Article 24 September Antifungal properties of cathelicidin LL current knowledge and future research directions Article 07 December Use our pre-submission checklist Avoid common mistakes on your manuscript.
Introduction Among 20 proteinogenic amino acids, nine are regarded as essential for humans: phenylalanine, valine, threonine, tryptophan, isoleucine, methionine, leucine, lysine, and histidine. Fungal biosynthetic pathways of human-essential amino acids and inhibitors of fungi-specific enzymes Fungal biosynthetic pathways of human-essential amino acids are in general identical or almost identical to the respective pathways operating in bacteria or plants.
The aspartate family l -Threonine, l -isoleucine, and l -methionine are the amino acids that belong to the so-called aspartate family. Full size image. Inhibitors of fungal enzymes of the threonine branch of the aspartate family pathways. Inhibitors of fungal enzymes of the methionine branch.
Inhibitors of fungal enzymes of the α-aminoadipate pathway. Inhibitors of enzymes involved in branched amino acid biosynthesis. Enzymes of human-non-essential amino acids biosynthesis in fungi and their inhibitors The glutamate family l -Glutamine, l -proline, and l -arginine are amino acids non-essential for humans.
Inhibitors of enzymes involved in glutamate and glutamine biosynthesis. Concluding remarks and future perspectives This review provides sample evidence that at least some of the enzymes catalyzing particular steps in biosynthetic pathways of amino acid biosynthesis could be successfully exploited as molecular targets for antifungal agents Table 1 ; Fig.
Table 1 The most promising antifungals inhibiting amino acid biosynthesis in fungi Full size table. References Abdo MR, Joseph P, Mortier J et al Anti-virulence strategy against Brucella suis : synthesis, biological evaluation and molecular modeling of selective histidinol dehydrogenase inhibitors.
Org Biomol Chem — CAS PubMed Google Scholar Adachi K, Covington A, Darveaux B et al Methods for the identification of inhibitors of pyrrolinecarboxylate reductase as antibiotics. Clin Microbiol Rev — CAS PubMed Central PubMed Google Scholar Aoki Y, Kongoh M, Nakamura M et al A new methionine antagonist that has antifungal activity: mode of action.
Jpn J Antibiot — Google Scholar Aoki Y, Kamiyama T, Fujii T et al Design of an antifungal methionine inhibitor not antagonized by methionine. Biol Pharm Bull — CAS PubMed Google Scholar Aoki Y, Yamamoto M, Hosseini-Mazinani SM et al Antifungal azoxybacilin exhibits activity by inhibiting gene expression of sulfite reductase.
Antimicrob Agents Chemother — CAS PubMed Central PubMed Google Scholar Aral B, Kamoun P The proline biosynthesis in living organisms.
Amino Acids — CAS Google Scholar Arevalo-Rodrigurez M, Xuewen P, Boeke JD, Heitman J FKBP12 controls aspartate pathway flux in saccharomyces cerevisiae to prevent toxic intermediate accumulation. Eucaryotic Cell — Google Scholar Baldwin B, Brownell K, Rees S et al The mode of action of the anilide fungicide SC Chem p Balhadère PV, Foster AJ, Talbot NJ Identification of pathogenicity mutants of the rice blast fungus Magnaporthe grisea by insertional mutagenesis.
Am Phytopathol Soc — Google Scholar Banerjee RV, Matthews RG Cobalamin-dependent methionine synthase. FASEB J — CAS PubMed Google Scholar Banerjee D, Burkard L, Panepinto JC Inhibition of nucleotide biosynthesis potentiates the antifungal activity of amphotericin B.
PLoS One 9:e PubMed Central PubMed Google Scholar Bareich DC, Nazi I, Wright G Simultaneous in vitro assay of the first four enzymes in the fungal aspartate pathway identifies a new class of aspartate kinase inhibitor. Chem Biol — CAS PubMed Google Scholar Becker J, Kauffman S, Hauser M et al Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model.
Proc Natl Acad Sci USA — CAS PubMed Central PubMed Google Scholar Beckmann N, Schafferer L, Schrettl M et al Characterization of the link between ornithine, arginine, polyamine and siderophore metabolism in Aspergillus fumigatus.
PLoS One 8:e CAS PubMed Central PubMed Google Scholar Bhattacharjee J α-Aminoadipate pathway for the biosynthesis of lysine in lower eukaryotes. Crit Rev Microbiol — CAS PubMed Google Scholar Birrell G, Giaever G, Chu A et al A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity.
Proc Natl Acad Sci USA — CAS PubMed Central PubMed Google Scholar Birrell G, Brown J, Wu H et al Transcriptional response of Saccharomyces cerevisiae to DNA-damaging agents does not identify the genes that protect against these agents.
Proc Natl Acad Sci USA — CAS PubMed Central PubMed Google Scholar Boguslawski G, Stetler D Aspects of physiology of Histoplasma capsulatum. Mycopathologia —24 CAS PubMed Google Scholar Borisova SA, Circello BT, Zhang JK et al Biosynthesis of rhizocticins, antifungal phosphonate oligopeptides produced by Bacillus subtilis ATC Chem Biol —37 CAS PubMed Central PubMed Google Scholar Braus G Aromatic amino acid biosynthesis in the yeast Saccharomyces cerevisiae : a model system for the regulation of a eukaryotic biosynthetic pathway.
Microbiol Mol Biol Rev — CAS Google Scholar Brown G, Bamford A, Bowyer J et al Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorganic Med Chem Lett — CAS Google Scholar Brunke S, Seider K, Almeida RS et al Candida glabrata tryptophan-based pigment production via the Ehrlich pathway.
Mol Microbiol —47 CAS PubMed Google Scholar Choudhury R, Punekar NS Competitive inhibition of glutamate dehydrogenase reaction. FEBS Lett — CAS PubMed Google Scholar Choudhury R, Noor S, Varadarajalu LP, Punekar NS Delineation of an in vivo inhibitor for Aspergillus glutamate dehydrogenase.
Enzyme Microb Technol — CAS PubMed Google Scholar Cunin R, Glansdorff N, Piérard A, Stalon V Biosynthesis and metabolism of arginine in bacteria. Microbiol Rev — CAS PubMed Central PubMed Google Scholar De Pascale G, Griffiths EJ, Shakya T et al Identification and characterization of new inhibitors of fungal homoserine kinase.
ChemBioChem — PubMed Google Scholar Duggleby R, Pang S, Yu H, Guddat LW Systematic characterization of mutations in yeast acetohydroxyacid synthase. Eur J Biochem — CAS PubMed Google Scholar Ejim L, Mirza IA, Capone C et al a New phenolic inhibitors of yeast homoserine dehydrogenase.
Bioorg Med Chem — CAS PubMed Google Scholar Ejim LJ, Costa VMD, Elowe NH et al b Cystathionine beta-lyase is important for virulence of Salmonella enterica serovar typhimurium. Infect Immun — CAS PubMed Central PubMed Google Scholar Ejim LJ, Blanchard JE, Koteva KP et al Inhibitors of bacterial cystathionine beta-lyase: leads for new antimicrobial agents and probes of enzyme structure and function.
J Med Chem — CAS PubMed Google Scholar Fasman G Handbook of biochemistry and molecular biology, third. CRC Pess, Cleveland Google Scholar Forlani G, Petrollino D, Fusetti M et al Δ1-Pyrrolinecarboxylate reductase as a new target for therapeutics: inhibition of the enzyme from Streptococcus pyogenes and effects in vivo.
Amino Acids — CAS PubMed Google Scholar Formica JV, Regelson W Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol — CAS PubMed Google Scholar Fritz R, Lanen C, Chapeland-Leclerc F, Leroux P Effect of the anilinopyrimidine fungicide pyrimethanil on the cystathionine β-lyase of Botrytis cinerea.
Pestic Biochem Physiol —65 CAS Google Scholar Fu J, Wu J, Jiang J et al Cystathionine γ-synthase is essential for methionine biosynthesis in Fusarium graminearum. Fungal Biol —21 CAS PubMed Google Scholar Fujita Y, Ukena E, Iefuji H et al Homocysteine accumulation causes a defect in purine biosynthesis: further characterization of Schizosaccharomyces pombe methionine auxotrophs.
Microbiology — CAS PubMed Google Scholar Fujiu M, Sawairi S, Shimada H et al Azoxybacilin, a novel antifungal agent produced by Bacillus cereus NR Jpn J Antibiot — CAS Google Scholar Gabriel I, Vetter ND, Palmer DRJ et al Homoisocitrate dehydrogenase from Candida albicans : properties, inhibition, and targeting by an antifungal pro-drug.
FEMS Yeast Res — CAS PubMed Google Scholar Gahungu M, Arguelles-Arias A, Fickers P et al Synthesis and biological evaluation of potential threonine synthase inhibitors: Rhizocticin A and Plumbemycin A.
Bioorg Med Chem — CAS PubMed Google Scholar Gibbons GF, Howard DH Arginine auxotrophs of Candida albicans deficient in argininosuccinate lyase. J Gen Microbiol — CAS PubMed Google Scholar González JC, Banerjee RV, Huang S et al Comparison of cobalamin-independent and cobalamin-dependent methionine synthases from Escherichia coli : two solutions to the same chemical problem.
Biochemistry — PubMed Google Scholar Gophna U, Bapteste E, Doolittle FW et al Evolutionary plasticity of methionine biosynthesis. Gene —57 CAS PubMed Google Scholar Grandoni JA, Marta PT, Schloss JV Inhibitors of branched-chain amino acid biosynthesis as potential antituberculosis agents.
J Antimicrob Chemother — CAS PubMed Google Scholar Gray S, Bhattacharjee J Biosynthesis of lysine in Saccharomyces cerevisiae : regulation of homoisocitrate synthase in analogue-resistant mutants.
J Gen Microbiol — CAS PubMed Google Scholar Gustavsson M, Ronne H Evidence that tRNA modifying enzymes are important in vivo targets for 5-fluorouracil in yeast. RNA — CAS PubMed Central PubMed Google Scholar Hamer L, Adachi K, Dezwaan T et al Methods for the identification of inhibitors of 3-isopropylmalate dehydratase as antibiotics.
Patent USA Han Y-K, Lee T, Han K-H et al Functional analysis of the homoserine O-acetyltransferase gene and its identification as a selectable marker in Gibberella zeae.
Curr Genet — CAS PubMed Google Scholar Hatanaka H, Ariga N, Nagai J, Katsuki H Accumulation of a sterol intermediate during reaction in the presence of homocysteine with cell-free extract of yeast.
Biochem Biophys Res Commun — Google Scholar Hoskins J, Butler J Evidence for distinct DNA- and RNA-based mechanisms of 5-fluorouracil cytotoxicity in Saccharomyces cerevisiae.
Yeast — CAS PubMed Google Scholar Hudson R, Daniel R L-Glutamate dehydrogenases: distribution, properties and mechanism. Mol Plant Microbe Interact — CAS PubMed Google Scholar Hwang SY, Berges DA, Taggart JJ, Gilvarg C Portage transport of sulfanilamide and sulfanilic acid. J Med Chem — CAS PubMed Google Scholar Jacques S, Mirza A, Ejim L et al Enzyme-assisted suicide: molecular basis for the antifungal activity of 5-hydroxyoxonorvaline by potent inhibition of homoserine dehydrogenase.
Chem Biol — CAS PubMed Google Scholar Jakubowski H Proofreading in vivo: editing of homocysteine by methionyl-tRNA synthetase in Escherichia coli.
Proc Natl Acad Sci USA — CAS PubMed Central PubMed Google Scholar Jakubowski H The determination of homocysteine-thiolactone in biological samples.
Anal Biochem — CAS PubMed Google Scholar Jakubowski H Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci — CAS PubMed Google Scholar Jones E, Fink G Regulation of amino acid and nucleotide biosynthesis.
Cold Spring Harbor Laboratory, New York, pp — Google Scholar Joshi CV, Pathan EK, Punekar NS et al A biochemical correlate of dimorphism in a zygomycete Benjaminiella poitrasii : characterization of purified NAD-dependent glutamate dehydrogenase, a target for antifungal agents.
Antonie Van Leeuwenhoek —36 CAS PubMed Google Scholar Kacprzak MM, Lewandowska I, Matthews RG, Paszewski A Transcriptional regulation of methionine synthase by homocysteine and choline in Aspergillus nidulans.
Biochem J — CAS PubMed Central PubMed Google Scholar Kim HS, Fay JC Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds. Proc Natl Acad Sci USA — CAS PubMed Central PubMed Google Scholar Kingsbury JM Cryptococcus neoformans Ilv2p confers resistance to sulfometuron methyl and is required for survival at 37 C and in vivo.
Microbiology — CAS PubMed Google Scholar Kingsbury JM, McCusker JH Threonine biosynthetic genes are essential in Cryptococcus neoformans. Microbiology — CAS PubMed Central PubMed Google Scholar Kingsbury JM, Goldstein AL, Mccusker JH Role of nitrogen and carbon transport, regulation, and metabolism genes for Saccharomyces cerevisiae survival in vivo.
Eucaryotic cell — CAS Google Scholar Kishore GM, Shah DM Amino acid biosynthesis inhibitors as herbicides. Annu Rev Biochem — CAS PubMed Google Scholar Kohlhaw GB Leucine biosynthesis in fungi: entering metabolism through the back door.
Microbiol Mol Biol Rev —15 CAS PubMed Central PubMed Google Scholar Krämer H-J, Podobinska M, Bartsch A et al Malassezin, a novel agonist of the aryl hydrocarbon receptor from the yeast Malassezia furfur , induces apoptosis in primary human melanocytes.
ChemBioChem — PubMed Google Scholar Kugler M, Loeffier W, Rapp C et al Rhizocticin A, an antifungal phosphono-oligopeptide of Bacillus subtilis ATC biological proporties.
Arch Microbiol — CAS PubMed Google Scholar Kur K, Gabriel I, Morschhäuser J et al Disruption of homocitrate synthase genes in Candida albicans affects growth but not virulence. Mycopathologia — CAS PubMed Google Scholar Kwon-Chung K, Rhodes JC Encapsulation and melanin formation as indicators of virulence in Cryptococcus neoformans.
Infect Immun — CAS PubMed Central PubMed Google Scholar Kwon-Chung K, Polacheck I, Popkin T Melanin lacking mutants of Cryptococcus neoformans and their virulence for mice. J Bacteriol — CAS PubMed Central PubMed Google Scholar Laber B, Lindell S, Pohlenz H Inactivation of Escherichia coli threonine synthase by DL-Zaminophosphonopentenoic acid.
Arch Microbiol — CAS PubMed Google Scholar Lee Y-T, Cui C-J, Chow EWL et al Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase.
J Med Chem — CAS PubMed Google Scholar Leroux P Recent developments in the mode of action of fungicides.
Pest Manag Sci — CAS Google Scholar Leroux P, Fritz R, Debieu D et al Mechanisms of resistance to fungicides in field strains of Botrytis cinerea. Pest Manag Sci — CAS PubMed Google Scholar Lewis A, Waterhouse C, Jacobs R Whole-blood an plasma amino acid analysis: gas-liquid and cation-exchange chromatography compared.
Clin Chem — CAS PubMed Google Scholar Liebmann B, Muhleisen T, Muller M et al Deletion of the Aspergillus fumigatus lysine biosynthesis gene lysF encoding homoaconitase leads to attenuated virulence in a low-dose mouse infection model of invasive aspergillosis.
Arch Microbiol — CAS PubMed Google Scholar Liu X-H, Shi Y-X, Ma Y et al Synthesis, antifungal activities and 3D-QSAR study of N- 5-substituted-1,3,4-thiadiazolyl cyclopropanecarboxamides.
Eur J Med Chem — CAS PubMed Google Scholar Lo S, Hamer L, Hamer JE Molecular characterization of a cystathionine β-synthase gene, CBS1 in Magnaporthe grisea. Eukaryot Cell — CAS PubMed Central PubMed Google Scholar Lo S, Montenegro-chamorro MV, Frank S et al Methods for the identification of inhibitors of asparagine synthase as antibiotics.
J Biol Chem — CAS PubMed Google Scholar Maresca B, Kobayashi G Dimorphism in Histoplasma capsulatum : a model for the study of cell differentiation in pathogenic fungi. Microbiol Rev — CAS PubMed Central PubMed Google Scholar Matsumoto H, Nagao J, Cho T, Kodama J Evaluation of pathogenicity of Candida albicans in germination-ready states using a silkworm infection model.
Jpn J Med Mycol — CAS Google Scholar McCammon M, Parks L Inhibition of sterol transmethylation by S-adenosylhomocysteine analogs. J Bacteriol — CAS PubMed Central PubMed Google Scholar Medoff G, Painter A, Kobayashi G Mycelial- to yeast phase transitions of the dimorphic fungi Blastomyces dermatitidis and Paracoccidioides brasiliensis.
J Bacteriol — CAS PubMed Central PubMed Google Scholar Milewska M, Prokop M, Gabriel I et al Antifungal activity of homoaconitate and homoisocitrate analogs.
Molecules — CAS PubMed Google Scholar Milewski S, Mignini F, Prasad R, Borowski E Unusual susceptibility of a multidrug-resistant yeast strain to peptidic antifungals unusual susceptibility of a multidrug-resistant yeast strain to peptidic antifungals.
Antimicrob Agents Chemother — CAS PubMed Central PubMed Google Scholar Morya VK, Kumari S, Kim E Imperative pathway analysis to identify the potential drug target for Aspergillus infection. Clin Proteomics —32 PubMed Central PubMed Google Scholar Motil K, Opekun A, Montandon C et al Leucine oxidation changes rapidly after dietary protein intake is altered in adult women but lysine flux is unchanged as is lysine incorporation into VLDL-apolipoprotein B J Nutr —51 CAS PubMed Google Scholar Namiki F, Matsunaga M, Okuda M et al Mutation of an arginine biosynthesis gene causes reduced pathogenicity in Fusarium oxysporum f.
Mol Plant Microbe Interact — CAS PubMed Google Scholar Nazi I, Scott A, Sham A et al Role of homoserine transacetylase as a new target for antifungal agents.
Antimicrob Agents Chemother — CAS PubMed Central PubMed Google Scholar Negredo A, Monteoliva L, Gil C et al Cloning, analysis and one-step disruption of the ARG5,6 gene of Candida albicans. Microbiology — CAS PubMed Google Scholar Noor S, Punekar N Allosteric NADP-glutamate dehydrogenase from Aspergilli : purification, characterization and implications for metabolic regulation at the carbon—nitrogen interface.
PLoS One 7:e CAS PubMed Central PubMed Google Scholar Pahwa S, Kaur S, Jain R, Roy N Structure based design of novel inhibitors for histidinol dehydrogenase from Geotrichum candidum. Bioorg Med Chem Lett — CAS PubMed Google Scholar Palmer DRJ, Balogh H, Ma G et al Synthesis and antifungal properties of compounds which target the α-aminoadipate pathway.
Pharmazie —98 CAS PubMed Google Scholar Parks L, Casey W Physiological implications of sterol biosynthesis in yeast. Annu Rev Microbiol — CAS PubMed Google Scholar Pascon RC, Ganous TM, Kingsbury JM et al Cryptococcus neoformans methionine synthase: expression analysis and requirement for virulence.
Microbiology — CAS PubMed Google Scholar Paszewski A, Brzywczy J, Natorff R Sulphur metabolism. Prog Ind Microbiol — CAS PubMed Google Scholar Peters J, Sypherd P Morphology-associated expression nicotinamide adenine dinucleotide-dependent glutamate dehydrogenase in Mucor racemosus. J Bacteriol — CAS PubMed Central PubMed Google Scholar Piotrowska M, Paszewski A Propargylglycine as a fungal inhibitor: effect on sulphur amino acid metabolism.
J Gen Microbiol — CAS Google Scholar Prasannan P, Suliman HS, Robertus JD Kinetic analysis of site-directed mutants of methionine synthase from Candida albicans.
Biochem Biophys Res Commun — CAS PubMed Google Scholar Ravanel S, Gakière B, Job D, Douce R The specific features of methionine biosynthesis and metabolism in plants. BMC Res Notes — CAS PubMed Central PubMed Google Scholar Rhodes JC, Howard DH Isolation and characterization of arginine auxotrophs of Cryptococcus neoformans.
Infect Immun — CAS PubMed Central PubMed Google Scholar Rhodes JC, Polacheck I, Kwon-Chung K Phenoloxidase activity and virulence in isogenic strains of Cryptococcus neoformans. Infect Immun — CAS PubMed Central PubMed Google Scholar Richie DL, Thompson KV, Studer C et al Identification and evaluation of novel acetolactate synthase inhibitors as antifungal agents.
Antimicrob Agents Chemother — CAS PubMed Central PubMed Google Scholar Rivalta I, Sultan MM, Lee N et al Allosteric pathways in imidazole glycerol phosphate synthase. PNAS — Google Scholar Rogers K, Boots M, Boots S Molecular interaction of six aromatic competitive inhibitors with bovine liver glutamate dehydrogenase.
Biochim Biophys Acta — CAS PubMed Google Scholar Schöbel F, Jacobsen ID, Brock M Evaluation of lysine biosynthesis as an antifungal drug target: biochemical characterization of Aspergillus fumigatus homocitrate synthase and virulence studies.
Eukaryot Cell — PubMed Central PubMed Google Scholar Seong K, Hou Z, Tracy M et al Random insertional mutagenesis identifies genes associated with virulence in the wheat scab fungus Fusarium graminearum.
Phytopathology — CAS PubMed Google Scholar Serlupi-Crescenzi O, Kurtz MB, Champe SP Developmental defects resulting from arginine auxotrophy in Aspergillus nidulans. J Gen Microbiol — CAS PubMed Google Scholar Shepherd MG Pathogenicity of morphological and auxotrophic mutants of Candida albicans in experimental infections.
Infect Immun — CAS PubMed Central PubMed Google Scholar Sieńko M, Paszewski A The metG gene of Aspergillus nidulans encoding cystathionine β-lyase: cloning and analysis. Curr Genet — PubMed Google Scholar Sierotzki H, Wullschleger J, Alt M et al Potential mode of resistance to anilinopyrimidine fungicides in Botrytis cinerea.
pp — Sousa S, McLaughlin M, Pereira S et al The ARO4 gene of Candida albicans encodes a tyrosine-sensitive DAHP synthase: evolution, functional conservation and phenotype of Aro3p- Aro4p-deficient mutants. Microbiology — CAS PubMed Google Scholar Suliman HS, Sawyer GM, Appling DR, Robertus JD Purification and properties of cobalamin-independent methionine synthase from Candida albicans and Saccharomyces cerevisiae.
Arch Biochem Biophys —63 CAS PubMed Google Scholar Suliman HS, Appling DR, Robertus JD The gene for cobalamin-independent methionine synthase is essential in Candida albicans : a potential antifungal target. Arch Biochem Biophys — CAS PubMed Central PubMed Google Scholar Tagliamonte A, Biggio G, Vargiu L, Gessa G Free tryptophan in serum controls brain tryptophan level and serotonin synthesis.
Life Sci — CAS Google Scholar Tang CM, Smith JM, Arst HN, Holden DW Virulence studies of Aspergillus nidulans mutants requiring lysine or p-aminobenzoic acid in invasive pulmonary aspergillosis.
Infect Immun — CAS PubMed Central PubMed Google Scholar Umbarger HE Amino acid biosynthesis and its regulation. Annu Rev Biochem — Google Scholar Whittington-Smith R, Baldwin B, Grindle M, Kelly S A molecular genetics approach to understanding the mode of action of a novel anilide fungicide.
p Yamaguchi H, Uchida K, Hiratani T et al RI, a new antifungal antibiotic. Ann N Y Acad Sci — CAS PubMed Google Scholar Yamaki H, Yamaguchi M, Imamura H et al The mechanism of antifungal action of S aminooxohydroxypentanoic acid, RI the inhibition of homoserine dehydrogenase in Saccharomyces cerevisiae.
Biochem Biophys Res Commun — CAS PubMed Google Scholar Yamamoto T, Eguchi T Thiahomoisocitrate: a highly potent inhibitor of homoisocitrate dehydrogenase involved in the α-aminoadipate pathway. Bioorganic Med Chem — CAS Google Scholar Yamamoto T, Miyazaki K, Eguchi T Substrate specificity analysis and inhibitor design of homoisocitrate dehydrogenase.
Bioorg Med Chem — CAS PubMed Google Scholar Yang Z, Pascon RC, Alspaugh JA et al Molecular and genetic analysis of the Cryptococcus neoformans MET3 gene and met3 mutant.
The advance on genome sequencing and computational methods for clustering homologous proteins has been helping the scientific community to reevaluate several aspects of basic biology. Here we have applied clustering of protein sequences chosen from two clades of organisms that are known to be autotrophic for the biosynthesis of Essential Amino Acids EAAs.
Furthermore, we searched for the enzymes responsible for nitrogen assimilation, incorporating ammonium into glutamate. Lack of cytoplasmic glutamate dehydrogenase leads to a dependency of amino acids consumption as the source of organic nitrogen, i.
The work presented here takes advantage of both the Seed Linkage software and a home-built UniProt Enriched KEGG Orthology database UEKO as source of information, to rapidly group homologues of fungi and plant amino acid sequences, respectively represented by Saccharomyces cerevisiae and Arabidopsis thaliana.
KEGG Orthology contains to date more than 1 million sequences from nearly 1, genomes and it was enriched by a procedure developed by our group to attain 2,, sequences from 25, organisms, constituting the UEKO database UniRef50 enriched KEGG Orthology database, to be published elsewhere and further distributed.
These numbers reinforce the relevance on the development of homologous searching capability, improving the ability of KEGG Orthology database to build a scenario for the biological processes of interest such as those presented here.
Moreover, on top of the search for homologues represented by circles in the Figures, a complementary search using the 31, clustered sequences allowed the investigation of all UniProt sequences, including fragments e.
UniProt accession B7QGP4, VIL1 from Arthropoda and some full length proteins not accessed by the initial search e. UniProt accession D3AYE6, complete protein K14, from Amoebozoa; actually a more recent version of KO already incorporates this entry.
It is important to notice that, in UniProt, the technical term fragment is applied to partial CDS sequences, a product of incompletely sequenced mRNA, as well as amino acid sequences modeled from the genome that lack initial methionine.
Thus they might represent additional evidence of the enzyme presence rather than a reminiscent pseudogene. One evidence collected as triangle claimed our attention, since it came from a clade bearing the complete genome of the well annotated organism Drosophila melanogaster Figure 1 , enzyme VIL1, phylum Arthropoda.
Thus, this represents a recent gene loss within a non functional pathway. The main interest of this work was to depict the evolution of amino acids essentiality, or heterotrophy.
Grouping organisms into phyla level allowed easy labeling of clades that comprise organisms with sequenced or draft genomes, as shown in Figures 1 , 2 and 3 , making it possible to infer deletion events distinctively in these clades.
It is important to notice that many phyla contain complete genomes, which allowed us to figure out the deletion process with more certainty. However, the picturing of the entire scenario allowed the analysis to be extended to the branched clades, although this requires additional caution on interpretation.
Even escaping the scope of this work, it suggests a demand for planned choice of genomes to be completely sequenced, since as clearly shown here we lack information from several phyla such as the ones represented with empty circles e. Cryptophyta, Haptophyta, Neocallimastigomycota and Glaucophyta.
Enzymes not found by our analysis requires further attention and search using more sensitive methods and detailed manual or even experimental analysis, to detect divergent sequences; in other words, the absence of evidence is not evidence of absence.
The scenario of amino acid auxotrophy supports the hypothesis of a Great Genomic Deletion model of amino acid biosynthesis in association with heterotrophy. This phenomenon has probably occurred several times, particularly at the origin of metazoans. This deletion has been likely associated with endosymbiotic relationships or with the development of systems specialized in nutrient absorption.
It seems that amino acid essentiality has been originated as a phenotypic loss of pathways early in Choanozoa, followed by multiple losses during metazoan evolution. Similar progresses of deletions occur closer to Heterokontophyta and Rhizaria, culminating in Apicomplexa.
Rhodophyta and Microsporidia also attain the auxotrophy. Moreover, remaining enzymes set apart from their original roles in amino acid biosynthetic metabolism seem to be more prone to evolutionary changes whilst enzymes present in complete pathways are more structurally conserved among distant phyla Figures 4 and 5.
Although a detailed investigation is needed, our preliminary analysis suggests that the copies which remained in metazoan genomes may have suffered subfunctionalization and sometimes this might have occurred in more ancestral organisms Figure 4 and additional files 2 and 3. Thus, in some sense, the orthologue enzyme might actually have been deleted in animals, and the divergent copy is the one remaining.
These divergent copies are sometimes named outparalogues. We are currently investigating substitution rate ratios and promoter elements in these genes. Subsequent deletion includes the enzymes implicated in nitrogen assimilation, which takes place just after the broad deletion of EAAs biosynthetic enzymes since except metazoans, other eukaryotic clades lack biosynthetic pathways and contains a nitrogen assimilative enzyme , as observed in more derived metazoans, but not Cnidaria.
Most Cnidaria are carnivorous, so one possibility is that Cnidaria may benefit from the assimilation of organic nitrogen under long periods of fasting, however this finding needs additional investigation.
Thus, the simplest explanation, is that the loss of nitrogen assimilative enzymes are related to lower selective pressure associated with the origin of the most heterotrophic organisms, animals.
To our knowledge this is the first initiative to clarify the complete scenario using powerful homologous grouping approaches and the total repertoire of sequenced genomes. The procedures described here provide a deeper analysis of amino acid and nitrogen heterotrophy among distinct taxa, extended to include the entire set of available proteins.
They show that amino acid essentiality was a broad phenomenon in eukaryotes, followed by the subsequent nutritional requirement of organic nitrogen, in animals. Seed Linkage requires BLAST version used was 2. Except where otherwise indicated, all fragmented proteins were removed from analyses by parsing the description line in FASTA files.
To enrich KEGG Orthology clusters with incomplete genome proteins UniRef50 Enriched KEGG Orthology UEKO was built with the procedure described by Fernandes et al [ 15 ].
A local MySQL database was used. Amino acid biosynthetic pathways were depicted with KEGG Pathway [ 30 ] manual inspection where UniProtKB identifiers for the enzymes used in this work could be retrieved for the model autotrophic organisms Saccharomyces cerevisiae , Arabidopsis thaliana and, for the archaeal lysine biosynthesis, Pyrococcus horikoshii.
The procedure starts with the selected sequences used as seed for Seed Linkage search in UniProtKB. The homologous cluster is enriched by i entries in KEGG Orthology KO belonging to the same KO where the seed is found and ii UEKO entries for this same KO.
All steps were conducted with MySQL consults and PERL v5. Results of search for homologues are represented by circles in the Figures.
For more details see additional file 4 : List of seed sequences and additional file 5 : List of clusters. Simple BLASTp analysis 10 e-value cutoff were also conducted with all UniProt proteins, comprising both UniProt complete and fragment entries, for each phylum against all clustered proteins in this project.
Results of this analysis are represented by triangles in the Figures. For phylogenetic analysis Prankster [ 32 ] was used for multiple sequence alignment and MEGA4 [ 33 ] to construct the phylogenetic tree using the neighbor-joining method [ 34 ] with bootstrap replicates.
Branch distances were obtained from phylogenetic trees, from the ancestors of Streptophyta, Dikarya and clades of metazoans. Only branches with significant bootstrap were used. With the distances, a ratio was calculated as below:.
where F from is either Streptophyta or Dikarya ancestor and T to is an animal ancestor see Figure 5 , X axis ; and S and D are the ancestors of Streptophyta and Dikarya, respectively.
Blair J, Shah P, Hedges SB: Evolutionary sequence analysis of complete eukaryote genomes. BMC Bioinformatics. Article PubMed PubMed Central Google Scholar. Cunchillos C, Lecointre G: Early steps of metabolism evolution inferred by cladistic analysis of amino acid catabolic pathways.
Comptes Rendus Biologies. Article PubMed CAS Google Scholar. Cunchillos C, Lecointre G: Ordering events of biochemical evolution. Hernández-Montes G, Díaz-Mejía JJ, Pérez-Rueda E, Segovia L: The hidden universal distribution of amino acid biosynthetic networks: a genomic perspective on their origins and evolution.
Genome Biol. Reeds PJ, Wahle KWJ, Haggarty P: Energy costs of protein and fatty acid synthesis. Proceedings of the Nutrition Society. Aoyagi Y, Tasaki I, Okumura J, Muramatsu T: Energy cost of whole-body protein synthesis measured in vivo in chicks. Comp Biochem Physiol A Comp Physiol.
Millward DJ: Metabolic Demands for Amino Acids and the Human Dietary Requirement: Millward and Rivers Revisited. The Journal of Nutrition.
PubMed CAS Google Scholar. Millward DJ, Rivers JP: The nutritional role of indispensable amino acids and the metabolic basis for their requirements. Eur J Clin Nutr. Elango R, Ball R, Pencharz P: Amino acid requirements in humans: with a special emphasis on the metabolic availability of amino acids.
Amino Acids. Payne SH, Loomis WF: Retention and Loss of Amino Acid Biosynthetic Pathways Based on Analysis of Whole-Genome Sequences. Eukaryotic Cell. Article PubMed CAS PubMed Central Google Scholar.
Consortium TU: The Universal Protein Resource UniProt in Nucleic Acids Research. Article Google Scholar. Tatusov R, Fedorova N, Jackson J, Jacobs A, Kiryutin B, Koonin E, Krylov D, Mazumder R, Mekhedov S, Nikolskaya A, et al: The COG database: an updated version includes eukaryotes.
Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M: The KEGG resource for deciphering the genome. Barbosa-Silva A, Satagopam V, Schneider R, Ortega JM: Clustering of cognate proteins among distinct proteomes derived from multiple links to a single seed sequence.
Fernandes GR, Barbosa DVC, Prosdocimi F, Pena IA, Santana-Santos L, Coelho Junior O, Barbosa-Silva A, Velloso HM, Mudado MA, Natale DA, et al: A procedure to recruit members to enlarge protein family databases--the building of UECOG UniRef-Enriched COG Database as a model.
Genetics and molecular research GMR. Suzek B, Huang H, McGarvey P, Mazumder R, Wu C: UniRef: comprehensive and non-redundant UniProt reference clusters. Katinka MD, Duprat S, Cornillot E, Metenier G, Thomarat F, Prensier G, Barbe V, Peyretaillade E, Brottier P, Wincker P, et al: Genome sequence and gene compaction of the eukaryote parasite Encephalitozoon cuniculi.
Prosdocimi F, Mudado MA, Ortega JM: A set of amino acids found to occur more frequently in human and fly than in plant and yeast proteomes consists of non-essential amino acids.
Computers in Biology and Medicine. Santana-Santos L, Prosdocimi F, Ortega JM: Essential amino acid usage and evolutionary nutrigenomics of eukaryotes--insights into the differential usage of amino acids in protein domains and extra-domains.
Miyazaki T, Miyazaki J, Yamane H, Nishiyama M: α-Aminoadipate aminotransferase from an extremely thermophilic bacterium, Thermus thermophilus. Velasco AM, Leguina JI, Lazcano A: Molecular Evolution of the Lysine Biosynthetic Pathways. Journal of Molecular Evolution.
Hudson AO, Bless C, Macedo P, Chatterjee SP, Singh BK, Gilvarg C, Leustek T: Biosynthesis of lysine in plants: evidence for a variant of the known bacterial pathways.
Biochim Biophys Acta. Nishida H, Nishiyama M, Kobashi N, Kosuge T, Hoshino T, Yamane H: A Prokaryotic Gene Cluster Involved in Synthesis of Lysine through the Amino Adipate Pathway: A Key to the Evolution of Amino Acid Biosynthesis.
Genome Research. Smith TJ, Schmidt T, Fang J, Wu J, Siuzdak G, Stanley CA: The Structure of Apo Human Glutamate Dehydrogenase Details Subunit Communication and Allostery. Journal of Molecular Biology. Andersson J, Roger A: Evolution of glutamate dehydrogenase genes: evidence for lateral gene transfer within and between prokaryotes and eukaryotes.
BMC Evolutionary Biology. Sonnhammer ELL, Koonin EV: Orthology, paralogy and proposed classification for paralog subtypes. Trends in Genetics. com ]. net ]. Kanehisa M: KEGG: From genes to biochemical pathways.
Bioinfomatics: Databases and Systems. Google Scholar. Löytynoja A, Goldman N: An algorithm for progressive multiple alignment of sequences with insertions.
Proceedings of the National Academy of Sciences of the United States of America. Tamura K, Dudley J, Nei M, Kumar S: MEGA4: Molecular Evolutionary Genetics Analysis MEGA Software Version 4.
Molecular Biology and Evolution. Saitou N, Nei M: The neighbor-joining method: a new method for reconstructing phylogenetic trees. Download references. Authors thank Dr. Darren Natale from PIR USA and Elisa Donnard LICR for critically reviewing this manuscript, Henrique Velloso for helping with taxonomic data and Laryssa Santos Queiroz with pathway inspections.
This work has been sponsored by the Brazilian Ministry of Education CAPES and Foundation for Research Support of Minas Gerais State FAPEMIG. This article has been published as part of BMC Genomics Volume 12 Supplement 4, Proceedings of the 6th International Conference of the Brazilian Association for Bioinformatics and Computational Biology X-meeting Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, , MG, Brazil.
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasilia, Brasilia, , DF, Brazil. Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, , RJ, Brazil.
You can also search for this author in PubMed Google Scholar. Correspondence to JM Ortega. The work presented here was carried out in collaboration between all authors. FP and JMO defined the research theme. RLMG developed the clustering procedure, created the dataset and conducted the experiments.
RLMG and GFR created the figures. RLMG, FP and LKM conducted phylogenetic analyses. GRF created the procedure of Uniref50 enrichment of KEGG Orthology database. HALR developed the PSI-BLAST validation method. JMO, FP and RLMG wrote the paper. All authors supervised and approved the final manuscript.
Additional file 1: Sequences and genome status distribution. Distribution of UniProtKB sequences among available genomes in three sequencing status groups: Complete, Draft plus In Progress and Incomplete.
PDF 57 KB. Additional file 2: Phylogenetic tree of 5-methyltetrahydropteroyltriglutamate--homocysteine methyltransferase M7. A phylogenetic tree of one of the four methyltransferases illustrated in Figure 1 for methionine biosynthesis.
Red circle represents Chordata and Cnidaria ancestor; Yellow circle Dikarya ancestor and green circle Streptophyta ancestor. PDF KB. Additional file 3: Phylogenetic tree of dihydrodipicolinate synthase K A phylogenetic tree of one of the enzymes illustrated in Figure 1 for lysine biosynthesis.
Red circle represents Arthropoda; Yellow circle Dikarya ancestor and green circle Streptophyta and Chlorophyta ancestor. Additional file 4: List of seed sequences.
A detailed list of sequences used as initiators for clustering process with UniProtKB identifier, NCBI taxonomy identifier and Enzyme Commission EC number.
PDF 95 KB. Additional file 5: List of clusters. A detailed list of created clusters for all enzymes with UniProtKB identifier and NCBI taxonomy identifier.
PDF 16 MB. Open Access This article is published under license to BioMed Central Ltd. Reprints and permissions. Guedes, R. et al. Amino acids biosynthesis and nitrogen assimilation pathways: a great genomic deletion during eukaryotes evolution.
BMC Genomics 12 Suppl 4 , S2 Download citation. Published : 22 December Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.
Skip to main content. Search all BMC articles Search. Download PDF. Volume 12 Supplement 4. Abstract Background Besides being building blocks for proteins, amino acids are also key metabolic intermediates in living cells.
Results Here, we applied a methodology based on clustering of homologous genes to seed sequences from autotrophic organisms Saccharomyces cerevisiae yeast and Arabidopsis thaliana plant. Conclusions A Great Deletion model is proposed here as a broad phenomenon generating the phenotype of amino acids essentiality followed, in metazoans, by organic nitrogen dependency.
Background Creation and analysis of groups of orthologous genes have been widely used for gene function prediction, evolutionary and divergence time studies [ 1 ].
Results Clustering homologues of amino acid biosynthetic enzymes To determine the distribution of amino acid biosynthetic enzymes, a homologue clustering process was developed to allow the use of both complete and incomplete genomes [ 14 , 15 ].
Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Figure 5. Discussion The advance on genome sequencing and computational methods for clustering homologous proteins has been helping the scientific community to reevaluate several aspects of basic biology.
Conclusions The procedures described here provide a deeper analysis of amino acid and nitrogen heterotrophy among distinct taxa, extended to include the entire set of available proteins. Procedure Amino acid biosynthetic pathways were depicted with KEGG Pathway [ 30 ] manual inspection where UniProtKB identifiers for the enzymes used in this work could be retrieved for the model autotrophic organisms Saccharomyces cerevisiae , Arabidopsis thaliana and, for the archaeal lysine biosynthesis, Pyrococcus horikoshii.
Phylogenetic analyses For phylogenetic analysis Prankster [ 32 ] was used for multiple sequence alignment and MEGA4 [ 33 ] to construct the phylogenetic tree using the neighbor-joining method [ 34 ] with bootstrap replicates.
Abbreviations COG: Cluster of Orthologous Groups EAAs: Essential Amino Acids GDH: Glutamate dehydrogenase KEGG: Kyoto Encyclopedia of Genes and Genomes KO: KEGG Orthology NEAAs: Non-Essential Amino Acids UEKO: UniRef50 Enriched KEGG Orthology.
References Blair J, Shah P, Hedges SB: Evolutionary sequence analysis of complete eukaryote genomes. Article PubMed PubMed Central Google Scholar Cunchillos C, Lecointre G: Early steps of metabolism evolution inferred by cladistic analysis of amino acid catabolic pathways.
Article PubMed CAS Google Scholar Cunchillos C, Lecointre G: Ordering events of biochemical evolution. Article PubMed CAS Google Scholar Hernández-Montes G, Díaz-Mejía JJ, Pérez-Rueda E, Segovia L: The hidden universal distribution of amino acid biosynthetic networks: a genomic perspective on their origins and evolution.
Article PubMed PubMed Central Google Scholar Reeds PJ, Wahle KWJ, Haggarty P: Energy costs of protein and fatty acid synthesis. Article PubMed CAS Google Scholar Aoyagi Y, Tasaki I, Okumura J, Muramatsu T: Energy cost of whole-body protein synthesis measured in vivo in chicks.
Article PubMed CAS Google Scholar Millward DJ: Metabolic Demands for Amino Acids and the Human Dietary Requirement: Millward and Rivers Revisited.
PubMed CAS Google Scholar Millward DJ, Rivers JP: The nutritional role of indispensable amino acids and the metabolic basis for their requirements. PubMed CAS Google Scholar Elango R, Ball R, Pencharz P: Amino acid requirements in humans: with a special emphasis on the metabolic availability of amino acids.
Article PubMed CAS Google Scholar Payne SH, Loomis WF: Retention and Loss of Amino Acid Biosynthetic Pathways Based on Analysis of Whole-Genome Sequences.
Article PubMed CAS PubMed Central Google Scholar Consortium TU: The Universal Protein Resource UniProt in Article Google Scholar Tatusov R, Fedorova N, Jackson J, Jacobs A, Kiryutin B, Koonin E, Krylov D, Mazumder R, Mekhedov S, Nikolskaya A, et al: The COG database: an updated version includes eukaryotes.
Article PubMed PubMed Central Google Scholar Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M: The KEGG resource for deciphering the genome. Article PubMed CAS PubMed Central Google Scholar Barbosa-Silva A, Satagopam V, Schneider R, Ortega JM: Clustering of cognate proteins among distinct proteomes derived from multiple links to a single seed sequence.
Article PubMed PubMed Central Google Scholar Fernandes GR, Barbosa DVC, Prosdocimi F, Pena IA, Santana-Santos L, Coelho Junior O, Barbosa-Silva A, Velloso HM, Mudado MA, Natale DA, et al: A procedure to recruit members to enlarge protein family databases--the building of UECOG UniRef-Enriched COG Database as a model.
Article PubMed CAS Google Scholar Suzek B, Huang H, McGarvey P, Mazumder R, Wu C: UniRef: comprehensive and non-redundant UniProt reference clusters. Article PubMed CAS Google Scholar Katinka MD, Duprat S, Cornillot E, Metenier G, Thomarat F, Prensier G, Barbe V, Peyretaillade E, Brottier P, Wincker P, et al: Genome sequence and gene compaction of the eukaryote parasite Encephalitozoon cuniculi.
Article PubMed CAS Google Scholar Prosdocimi F, Mudado MA, Ortega JM: A set of amino acids found to occur more frequently in human and fly than in plant and yeast proteomes consists of non-essential amino acids.
Aspergillus Gut health foods is the Carbohydrate and blood sugar levels prevalent filamentous fungal pathogen of Gut health foods, caid either severe allergic bronchopulmonary aspergillosis Eating disorder recovery support often fatal invasive pulmonary aspergillosis IPA in individuals with hyper- or hypo-immune acld, respectively. Freshly Picked Oranges is primarily initiated axid the inhalation of the avid airborne conidia—the initial inoculum produced by A. fumigatus —which are complete developmental units with an ability to exploit diverse environments, ranging from agricultural composts to animal lungs. One such nutritional limitation is the availability of aromatic amino acids AAAs as animals lack the enzymes to synthesize tryptophan Trp and phenylalanine and only produce tyrosine from dietary phenylalanine. However, A. fumigatus produces all three AAAs through the shikimate—chorismate pathway, where they play a critical role in fungal growth and development and in yielding many downstream metabolites.
Wacker, Ihre Phrase wird nützlich sein
Mir ist nicht klar.
entschuldigen Sie, die Mitteilung ist gelöscht