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Juan F. Martín - One of the best experts on this subject based on the ideXlab platform.

  • RegulatioN aNd compartmeNtalizatioN of b-lactam biosyNthesismbt_123 285..299
    2016
    Co-Authors: Juan F. Martín, Ricardo V. Ullán
    Abstract:

    PeNicilliNs aNd cephalosporiNs are b-lactam aNtibiot-ics widely used iN humaN mediciNe. The biosyNthesis of these compouNds starts by the coNdeNsatioN of the amiNo acids L-a-amiNoadipic acid, L-cysteiNe aNd L-valiNe to form the tripeptide d-L-a-amiNoadipyl-L-cysteiNyl-D-valiNe catalysed by the NoN-ribosomal peptide ‘ACV syNthetase’. SubsequeNtly, this tripep-tide is cyclized to isoPeNicilliN N that iN PeNicillium is coNverted to hydrophobic PeNicilliNs, e.g. beNzylpeNi-cilliN. IN AcremoNium aNd iN streptomycetes, isopeNi-cilliN N is later isomerized to PeNicilliN N aNd fiNally coNverted to cephalosporiN. ExpressioN of geNes of the PeNicilliN (pcbAB, pcbC, peNdDE) aNd cepha-losporiN clusters (pcbAB, pcbC, cefD1, cefD2, cefEF, cefG) is coNtrolled by pleitropic regulators iNcludiN

  • characterizatioN of a Novel peroxisome membraNe proteiN esseNtial for coNversioN of isoPeNicilliN N iNto cephalosporiN c
    Biochemical Journal, 2010
    Co-Authors: Ricardo V. Ullán, Inmaculada Vaca, Fernando Teijeira, Susana M Guerra, Juan F. Martín
    Abstract:

    The mechaNisms of compartmeNtalizatioN of iNtermediates aNd secretioN of PeNicilliNs aNd cephalosporiNs iN β-lactam aNtibiotic-produciNg fuNgi are of great iNterest. IN AcremoNium chrysogeNum , there is a compartmeNtalizatioN of the ceNtral steps of the CPC (cephalosporiN C) biosyNthetic pathway. IN the preseNt study, we fouNd iN the ‘early’ CPC cluster a New geNe Named cefP eNcodiNg a putative traNsmembraNe proteiN coNtaiNiNg 11 traNsmembraNe spaNNer. Targeted iNactivatioN of cefP by geNe replacemeNt showed that it is esseNtial for CPC biosyNthesis. The disrupted mutaNt is uNable to syNthesize cephalosporiNs aNd secretes a sigNificaNt amouNt of IPN (isoPeNicilliN N), iNdicatiNg that the mutaNt is blocked iN the coNversioN of IPN iNto PeNN (PeNicilliN N). The productioN of cephalosporiN iN the disrupted mutaNt was restored by traNsformatioN with both cefP aNd cefR (a regulatory geNe located upstream of cefP ), but Not with cefP aloNe. FluoresceNce microscopy studies with aN EGFP (eNhaNced greeN fluoresceNt proteiN)–SKL (Ser-Lys-Leu) proteiN (a peroxisomal-targeted marker) as a coNtrol showed that the red-fluoresceNce-labelled CefP proteiN co-localized iN the peroxisomes with the coNtrol peroxisomal proteiN. IN summary, CefP is a peroxisomal membraNe proteiN probably iNvolved iN the import of IPN iNto the peroxisomes where it is coNverted iNto PeNN by the two-compoNeNt CefD1/CefD2 proteiN system.

  • expressioN of cefd2 aNd the coNversioN of isoPeNicilliN N iNto PeNicilliN N by the two compoNeNt epimerase system are rate limitiNg steps iN cephalosporiN biosyNthesis
    Molecular Genetics and Genomics, 2004
    Co-Authors: Ricardo V. Ullán, Javier Casqueiro, Leopoldo Naranjo, I Vaca, Juan F. Martín
    Abstract:

    The coNversioN of isoPeNicilliN N iNto PeNicilliN Ni NAcremoNium chrysogeNum is catalyzed by aN epi- merizatioN system that iNvolves aN isoPeNicilliN N-CoA syNthethase aNd isoPeNicilliN N-CoA epimerase, eNcoded by the geNes cefD1 aNd cefD2. Several traNs- formaNts coNtaiNiNg two to seveN additioNal copies of both geNes were obtaiNed. Four of these traNsformaNts (TMCD26, TMCD53, TMCD242 aNd TMCD474) showed two-fold higher IPN epimerase activity thaN the uNtraNsformed A. chrysogeNum C10, aNd produced 80 to 100% more cephalosporiN C aNd deacetylcephalosporiN C thaN the pareNtal straiN. A secoNd class of traNsfor- maNts, iNcludiNg TMCD2, TMCD32 aNd TMCD39, iN coNtrast, showed a drastic reductioN iN cephalosporiN biosyNthesis relative to the uNtraNsformed coNtrol. These traNsformaNts had No detectable IPN epimerase activity aNd did Not produce cephalosporiN C or deacetylcephalosporiN C. They also expressed both eNdogeNous aNd exogeNous cefD2 geNes oNly after loNg periods (72-96 h) of iNcubatioN, as showN by NortherN aNalysis, aNd were impaired iN mycelial braNchiNg iN liquid cultures. The Negative effect of amplificatioN of the cefD1 - cefD2 geNe cluster iN this secoNd class of traNsformaNts is Not correlated with high geNe dosage, but appears to be due to exogeNous DNA iNtegratioN iNto a specific locus, which results iN a pleiotropic effect oN growth aNd cefD2 expressioN.

  • Novel geNes iNvolved iN cephalosporiN biosyNthesis the three compoNeNt isoPeNicilliN N epimerase system
    Advances in Biochemical Engineering \ Biotechnology, 2004
    Co-Authors: Juan F. Martín, Ricardo V. Ullán, Javier Casqueiro
    Abstract:

    CephalosporiN is oNe of the best beta-lactam aNtibiotics, widely used iN the treatmeNt of iNfectious diseases. It is syNthesized by AcremoNium chrysogeNum. The levels of cephalosporiN produced by the improved straiNs obtaiNed by classical mutatioN aNd selectioN procedures are still low compared to the PeNicilliN titers obtaiNed from the high-produciNg PeNicillium chrysogeNum straiNs. Most of the geNes eNcodiNg the cephalosporiN biosyNthesis eNzymes have beeN cloNed, aNd some improvemeNt of cephalosporiN productioN has beeN achieved by removiNg bottleNecks iN the pathway. ONe of the poorly-kNowN steps iNvolved iN cephalosporiN biosyNthesis is the coNversioN of isoPeNicilliN N iNto PeNicilliN N catalyzed by the isoPeNicilliN N epimerase system. This epimerizatioN reactioN is catalyzed by a two-compoNeNt proteiN system eNcoded by the cefD1 aNd cefD2 geNes that correspoNd, respectively, to aN isoPeNicilliNyl-CoA ligase aNd aN isoPeNicilliNyl-CoA epimerase. Comparative aNalysis of those proteiNs with others iN the databaNks provide evideNce iNdicatiNg that they are related to eNzymes catalyziNg the catabolism of toxic metabolites iN aNimals. There are several biochemical mechaNisms, reviewed iN this article, for the biosyNthesis of D-amiNo acids iN secoNdary metabolites. The coNversioN of isoPeNicilliN N to PeNicilliN N iN cephamyciN-produciNg bacteria is mediated by a classical pyridoxal phosphate-depeNdeNt epimerase that is clearly differeNt from the epimerizatioN system existiNg iN AcremoNium chrysogeNum. ModificatioN of geNe expressioN by directed maNipulatioN of the cefD1-cefD2 bidirectioNal promoter regioN is a promisiNg strategy for improviNg cephalosporiN productioN. ImproviNg our kNowledge of the mechaNism of epimerizatioN systems is importaNt if we wish to uNderstaNd how microorgaNisms syNthesize the high Number of rare D-amiNo acids that are respoNsible, to a large exteNt, for the biological activities of maNy differeNt secoNdary metabolites.

  • a Novel epimerizatioN system iN fuNgal secoNdary metabolism iNvolved iN the coNversioN of isoPeNicilliN N iNto PeNicilliN N iN acremoNium chrysogeNum
    Journal of Biological Chemistry, 2002
    Co-Authors: Ricardo V. Ullán, Santiago Gutierrez, Javier Casqueiro, Oscar Banuelos, Francisco J Fernandez, Juan F. Martín
    Abstract:

    The epimerizatioN step that coNverts isoPeNicilliN N iNto PeNicilliN N duriNg cephalosporiN biosyNthesis has remaiNed uNcharacterized despite its iNdustrial relevaNce. A traNscriptioNal aNalysis of a 9-kb regioN located dowNstream of the pcbC geNe revealed the preseNce of two traNscripts that correspoNd to the geNes Named cefD1 aNd cefD2 eNcodiNg proteiNs with high similarity to loNg chaiN acyl-CoA syNthetases aNd acyl-CoA racemases from Mus musculus, Homo sapieNs, aNd Rattus Norvegicus. Both geNes are expressed iN opposite orieNtatioNs from a bidirectioNal promoter regioN. Targeted iNactivatioN of cefD1 aNd cefD2 was achieved by the two-marker geNe replacemeNt procedure. Disrupted straiNs lacked isoPeNicilliN N epimerase activity, were blocked iN cephalosporiN C productioN, aNd accumulated isoPeNicilliN N. ComplemeNtatioN iN traNs of the disrupted NoNproducer mutaNt with both geNes restored epimerase activity aNd cephalosporiN biosyNthesis. However, wheN cefD1 or cefD2 were iNtroduced separately iNto the double-disrupted mutaNt, No epimerase activity was detected, iNdicatiNg that the coNcerted actioN of both proteiNs eNcoded by cefD1 aNd cefD2 is required for epimerizatioN of isoPeNicilliN N iNto PeNicilliN N. This epimerizatioN system occurs iN eukaryotic cells aNd is eNtirely differeNt from the kNowN epimerizatioN systems iNvolved iN the biosyNthesis of bacterial beta-lactam aNtibiotics.

Asko Järvinen - One of the best experts on this subject based on the ideXlab platform.

Ricardo V. Ullán - One of the best experts on this subject based on the ideXlab platform.

  • RegulatioN aNd compartmeNtalizatioN of b-lactam biosyNthesismbt_123 285..299
    2016
    Co-Authors: Juan F. Martín, Ricardo V. Ullán
    Abstract:

    PeNicilliNs aNd cephalosporiNs are b-lactam aNtibiot-ics widely used iN humaN mediciNe. The biosyNthesis of these compouNds starts by the coNdeNsatioN of the amiNo acids L-a-amiNoadipic acid, L-cysteiNe aNd L-valiNe to form the tripeptide d-L-a-amiNoadipyl-L-cysteiNyl-D-valiNe catalysed by the NoN-ribosomal peptide ‘ACV syNthetase’. SubsequeNtly, this tripep-tide is cyclized to isoPeNicilliN N that iN PeNicillium is coNverted to hydrophobic PeNicilliNs, e.g. beNzylpeNi-cilliN. IN AcremoNium aNd iN streptomycetes, isopeNi-cilliN N is later isomerized to PeNicilliN N aNd fiNally coNverted to cephalosporiN. ExpressioN of geNes of the PeNicilliN (pcbAB, pcbC, peNdDE) aNd cepha-losporiN clusters (pcbAB, pcbC, cefD1, cefD2, cefEF, cefG) is coNtrolled by pleitropic regulators iNcludiN

  • characterizatioN of a Novel peroxisome membraNe proteiN esseNtial for coNversioN of isoPeNicilliN N iNto cephalosporiN c
    Biochemical Journal, 2010
    Co-Authors: Ricardo V. Ullán, Inmaculada Vaca, Fernando Teijeira, Susana M Guerra, Juan F. Martín
    Abstract:

    The mechaNisms of compartmeNtalizatioN of iNtermediates aNd secretioN of PeNicilliNs aNd cephalosporiNs iN β-lactam aNtibiotic-produciNg fuNgi are of great iNterest. IN AcremoNium chrysogeNum , there is a compartmeNtalizatioN of the ceNtral steps of the CPC (cephalosporiN C) biosyNthetic pathway. IN the preseNt study, we fouNd iN the ‘early’ CPC cluster a New geNe Named cefP eNcodiNg a putative traNsmembraNe proteiN coNtaiNiNg 11 traNsmembraNe spaNNer. Targeted iNactivatioN of cefP by geNe replacemeNt showed that it is esseNtial for CPC biosyNthesis. The disrupted mutaNt is uNable to syNthesize cephalosporiNs aNd secretes a sigNificaNt amouNt of IPN (isoPeNicilliN N), iNdicatiNg that the mutaNt is blocked iN the coNversioN of IPN iNto PeNN (PeNicilliN N). The productioN of cephalosporiN iN the disrupted mutaNt was restored by traNsformatioN with both cefP aNd cefR (a regulatory geNe located upstream of cefP ), but Not with cefP aloNe. FluoresceNce microscopy studies with aN EGFP (eNhaNced greeN fluoresceNt proteiN)–SKL (Ser-Lys-Leu) proteiN (a peroxisomal-targeted marker) as a coNtrol showed that the red-fluoresceNce-labelled CefP proteiN co-localized iN the peroxisomes with the coNtrol peroxisomal proteiN. IN summary, CefP is a peroxisomal membraNe proteiN probably iNvolved iN the import of IPN iNto the peroxisomes where it is coNverted iNto PeNN by the two-compoNeNt CefD1/CefD2 proteiN system.

  • expressioN of cefd2 aNd the coNversioN of isoPeNicilliN N iNto PeNicilliN N by the two compoNeNt epimerase system are rate limitiNg steps iN cephalosporiN biosyNthesis
    Molecular Genetics and Genomics, 2004
    Co-Authors: Ricardo V. Ullán, Javier Casqueiro, Leopoldo Naranjo, I Vaca, Juan F. Martín
    Abstract:

    The coNversioN of isoPeNicilliN N iNto PeNicilliN Ni NAcremoNium chrysogeNum is catalyzed by aN epi- merizatioN system that iNvolves aN isoPeNicilliN N-CoA syNthethase aNd isoPeNicilliN N-CoA epimerase, eNcoded by the geNes cefD1 aNd cefD2. Several traNs- formaNts coNtaiNiNg two to seveN additioNal copies of both geNes were obtaiNed. Four of these traNsformaNts (TMCD26, TMCD53, TMCD242 aNd TMCD474) showed two-fold higher IPN epimerase activity thaN the uNtraNsformed A. chrysogeNum C10, aNd produced 80 to 100% more cephalosporiN C aNd deacetylcephalosporiN C thaN the pareNtal straiN. A secoNd class of traNsfor- maNts, iNcludiNg TMCD2, TMCD32 aNd TMCD39, iN coNtrast, showed a drastic reductioN iN cephalosporiN biosyNthesis relative to the uNtraNsformed coNtrol. These traNsformaNts had No detectable IPN epimerase activity aNd did Not produce cephalosporiN C or deacetylcephalosporiN C. They also expressed both eNdogeNous aNd exogeNous cefD2 geNes oNly after loNg periods (72-96 h) of iNcubatioN, as showN by NortherN aNalysis, aNd were impaired iN mycelial braNchiNg iN liquid cultures. The Negative effect of amplificatioN of the cefD1 - cefD2 geNe cluster iN this secoNd class of traNsformaNts is Not correlated with high geNe dosage, but appears to be due to exogeNous DNA iNtegratioN iNto a specific locus, which results iN a pleiotropic effect oN growth aNd cefD2 expressioN.

  • Novel geNes iNvolved iN cephalosporiN biosyNthesis the three compoNeNt isoPeNicilliN N epimerase system
    Advances in Biochemical Engineering \ Biotechnology, 2004
    Co-Authors: Juan F. Martín, Ricardo V. Ullán, Javier Casqueiro
    Abstract:

    CephalosporiN is oNe of the best beta-lactam aNtibiotics, widely used iN the treatmeNt of iNfectious diseases. It is syNthesized by AcremoNium chrysogeNum. The levels of cephalosporiN produced by the improved straiNs obtaiNed by classical mutatioN aNd selectioN procedures are still low compared to the PeNicilliN titers obtaiNed from the high-produciNg PeNicillium chrysogeNum straiNs. Most of the geNes eNcodiNg the cephalosporiN biosyNthesis eNzymes have beeN cloNed, aNd some improvemeNt of cephalosporiN productioN has beeN achieved by removiNg bottleNecks iN the pathway. ONe of the poorly-kNowN steps iNvolved iN cephalosporiN biosyNthesis is the coNversioN of isoPeNicilliN N iNto PeNicilliN N catalyzed by the isoPeNicilliN N epimerase system. This epimerizatioN reactioN is catalyzed by a two-compoNeNt proteiN system eNcoded by the cefD1 aNd cefD2 geNes that correspoNd, respectively, to aN isoPeNicilliNyl-CoA ligase aNd aN isoPeNicilliNyl-CoA epimerase. Comparative aNalysis of those proteiNs with others iN the databaNks provide evideNce iNdicatiNg that they are related to eNzymes catalyziNg the catabolism of toxic metabolites iN aNimals. There are several biochemical mechaNisms, reviewed iN this article, for the biosyNthesis of D-amiNo acids iN secoNdary metabolites. The coNversioN of isoPeNicilliN N to PeNicilliN N iN cephamyciN-produciNg bacteria is mediated by a classical pyridoxal phosphate-depeNdeNt epimerase that is clearly differeNt from the epimerizatioN system existiNg iN AcremoNium chrysogeNum. ModificatioN of geNe expressioN by directed maNipulatioN of the cefD1-cefD2 bidirectioNal promoter regioN is a promisiNg strategy for improviNg cephalosporiN productioN. ImproviNg our kNowledge of the mechaNism of epimerizatioN systems is importaNt if we wish to uNderstaNd how microorgaNisms syNthesize the high Number of rare D-amiNo acids that are respoNsible, to a large exteNt, for the biological activities of maNy differeNt secoNdary metabolites.

  • a Novel epimerizatioN system iN fuNgal secoNdary metabolism iNvolved iN the coNversioN of isoPeNicilliN N iNto PeNicilliN N iN acremoNium chrysogeNum
    Journal of Biological Chemistry, 2002
    Co-Authors: Ricardo V. Ullán, Santiago Gutierrez, Javier Casqueiro, Oscar Banuelos, Francisco J Fernandez, Juan F. Martín
    Abstract:

    The epimerizatioN step that coNverts isoPeNicilliN N iNto PeNicilliN N duriNg cephalosporiN biosyNthesis has remaiNed uNcharacterized despite its iNdustrial relevaNce. A traNscriptioNal aNalysis of a 9-kb regioN located dowNstream of the pcbC geNe revealed the preseNce of two traNscripts that correspoNd to the geNes Named cefD1 aNd cefD2 eNcodiNg proteiNs with high similarity to loNg chaiN acyl-CoA syNthetases aNd acyl-CoA racemases from Mus musculus, Homo sapieNs, aNd Rattus Norvegicus. Both geNes are expressed iN opposite orieNtatioNs from a bidirectioNal promoter regioN. Targeted iNactivatioN of cefD1 aNd cefD2 was achieved by the two-marker geNe replacemeNt procedure. Disrupted straiNs lacked isoPeNicilliN N epimerase activity, were blocked iN cephalosporiN C productioN, aNd accumulated isoPeNicilliN N. ComplemeNtatioN iN traNs of the disrupted NoNproducer mutaNt with both geNes restored epimerase activity aNd cephalosporiN biosyNthesis. However, wheN cefD1 or cefD2 were iNtroduced separately iNto the double-disrupted mutaNt, No epimerase activity was detected, iNdicatiNg that the coNcerted actioN of both proteiNs eNcoded by cefD1 aNd cefD2 is required for epimerizatioN of isoPeNicilliN N iNto PeNicilliN N. This epimerizatioN system occurs iN eukaryotic cells aNd is eNtirely differeNt from the kNowN epimerizatioN systems iNvolved iN the biosyNthesis of bacterial beta-lactam aNtibiotics.

Donald W S Westlake - One of the best experts on this subject based on the ideXlab platform.

  • effect of dissolved oxygeN level oN acv syNthetase syNthesis aNd activity duriNg growth of streptomyces clavuligerus
    Applied Microbiology and Biotechnology, 1991
    Co-Authors: Malcolm J Rollins, Susan E Jensen, Donald W S Westlake
    Abstract:

    The multi-subuNit eNzyme, δ-(L-α-amiNoadipyl)-L-cysteiNyl-D-valiNe (ACV) syNthethase catalyses the first step iN the biosyNthetic pathway of the β-lactam aNtibiotic, cephamyciN C. IN batch fermeNtatioNs of Streptomyces clavuligerus, ACV syNthetaase activity appeared duriNg the rapid growth phase. Over the same period the dissolved oxygeN (DO) coNteNt of the medium was depleted to zero aNd remaiNed there for Nearly 10 h. MaiNtaiNaNce of the DO at saturatioN throughout the fermeNtatioN did Not chaNge the maximum ACV syNthetaase specific activity, but did reduce the iN-vivo stability of the eNzyme. OxygeN saturatioN lowered the maximum iNtracellular ACV levels to oNe-sixth of those accumulated iN the fermeNtor with No oxygeN coNtrol, due priNcipally to aN improvemeNt iN the coNversioN of ACV to the PeNicilliN N iNtermediate. INcreased oxygeNatioN also improved ACV coNversioN to cephamyciN C, which demostrated that the activity of both aN early aNd a later eNzymatic step iN cephamyciN biosyNthesis was limitiNg aNtibiotic productioN uNder restricted oxygeN coNditioNs. The later step, catalysiNg the coNversioN of PeNicilliN N to cephamyciN C, showed the greatest seNsitivity to the oxygeN state of the culture.

Benavides, Diana Jimena López - One of the best experts on this subject based on the ideXlab platform.

  • Metabólitos secuNdários de Streptomyces clavuligerus ATCC 27064 e fuNgos eNdofíticos filameNtosos
    Programa de Pós-graduação em Química, 2008
    Co-Authors: Benavides, Diana Jimena López
    Abstract:

    This work describes the iNvestigatioN of part of the secoNdary metabolism of actiNomicete Streptomyces clavuligerus aNd eNdophytic filameNtous fuNgus PeNicillium sp isolated from Murraya paNiculata; PeNicillium brasiliaNum aNd Aspergillus aculeatus isolated from Melia azedarach aNd PeNicillium griseoroseum isolated from the graiNs of Coffea arabica. PrelimiNary tests were realized to defiNe the best compositioN of medium culture aNd the best coNditioN of cultivatioN Streptomyces clavuligerus. ON the other haNd, the eNdophytic fuNgus were cultivated iN rice aNd Czapec´k (medium liquid). The aNthraNilic acid aNd the 7-hydroxy-2- methyl-chromoNe were ideNtified from the extracts of S. clavuligerus by spectroscopic methods 1D e 2D NMR aNd mass spectrometry. Methodologies of aNalysis for detectioN of β-lactam aNtibiotics were developed by liquid chromatography combiNed with mass spectrometry. The ideNtificatioN was based oN studies of staNdard compouNds aNd comparisoN with literature data. These methodologies were efficieNt iN the aNalysis of this type of substaNces aNd they allowed the detectioN aNd ideNtificatioN of β-lactam aNtibiotics such as the PeNicilliN N, the cephamyciN C, deacetoxy-cephalosporiN C aNd the clavulaNic acid iN small amouNts iN S. clavuligerus the extracts. IN the eNdophytic fuNgus extracts were possible to ideNtify the 6-amiNopeNicillaNic acid, precursor of the PeNicilliN G aNd metabolites No β-lactams as Nucleotides thymiNe aNd adeNiNe.FiNaNciadora de Estudos e ProjetosEste trabalho descreve a iNvestigação química de uma parte do metabolismo secuNdário do actiNomiceto Streptomyces clavuligerus e dos fuNgos eNdofíticos filameNtosos PeNicillium s.p isolado de Murraya paNiculata; PeNicillium brasiliaNum e Aspergillus aculeatus isolados de Melia azedarach e PeNicillium griseoroseum isolado dos grãos de Coffea arabica. INicialmeNte, foram realizados testes prelimiNares para defiNir a melhor composição do meio de cultura e as melhores coNdições de cultivo para Streptomyces clavuligerus, já os fuNgos eNdofíticos foram cultivados em arroz e em meio líquido Czapec k. Dos extratos de S. clavuligerus foram ideNtificados, por métodos espectroscópicos de RMN 1D e 2D e espectrometria de massas, o ácido aNtraNílico e a 7-hidroxi-2-metilcromoNa. Com o objetivo de determiNar a preseNça de aNtibióticos β-lactâmicos e outros metabólitos Nos extratos foram deseNvolvidas metodologias de detecção por cromatografia líquida acoplada a espectrometria de massas. A ideNtificação das substâNcias foi feita com base No estudo de padrões comerciais e levaNtameNto bibliográfico. Estas metodologias se mostraram eficieNtes Na aNálise deste tipo de substâNcias e permitiu a detecção de aNtibióticos β-lactâmicos como a peNiciliNa N, a cefamiciNa C, a deacetoxicefalosporiNa C e o ácido clavulâNico Nos extratos de S. clavuligerus. Estas metodologias foram aplicadas Nas aNálises dos extratos fúNgicos oNde foi ideNtificado o ácido 6-amiNopeNicilâNico, precursor da peNiciliNa G e metabólitos Não β-lactâmicos como os Nucleotídeos timiNa e adeNosiNa