新靶点PPTase抗真菌药物的研究进展
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摘要
磷酸泛酰巯基乙胺基转移酶(phosphopantetheinyl transferase,PPTase)可修饰脂肪酸合成酶、聚酮合成酶和非核糖体多肽合成酶复合体中的载体蛋白,使其由无活性形式转变成活性形式,同时它参与脂肪酸、聚酮、非核糖体多肽的合成,因而可作为抗菌药物有效的且颇具研究价值的新靶点。本文由PPTase的分类展开,进而阐述各类别发现的药物,综述该研究领域的最新进展,为新型抗真菌药物的研发提供参考。
Phosphopantetheinyl transferase(PPTase) can modify fatty acid synthase,polyketide synthase and the carrier protein of non-ribosomal peptide synthases.It can transfer the 4-phosphopantetheine on coenzyme A to the side chain hydroxyl of conservative serine residue.Also,it turns the carrier protein from the inactive form of apo-to active protein(holo-).At the same time,it involves in the synthesis of fatty acids,polykethers,and ribosomal peptides.All three substances are closely related to the virulence and viability of microorganisms,making them a powerful new target for antibacterial drugs.Here the drugs found in various categories from the classification of PPTase and the latest progress in the related research were reviewed,thus provide a reference for the research and development of new antifungal drugs.
Phosphopantetheinyl transferase(PPTase) can modify fatty acid synthase,polyketide synthase and the carrier protein of non-ribosomal peptide synthases.It can transfer the 4-phosphopantetheine on coenzyme A to the side chain hydroxyl of conservative serine residue.Also,it turns the carrier protein from the inactive form of apo-to active protein(holo-).At the same time,it involves in the synthesis of fatty acids,polykethers,and ribosomal peptides.All three substances are closely related to the virulence and viability of microorganisms,making them a powerful new target for antibacterial drugs.Here the drugs found in various categories from the classification of PPTase and the latest progress in the related research were reviewed,thus provide a reference for the research and development of new antifungal drugs.
引文
[1] 刘祚军,张部昌,马清钧.磷酸泛酰巯基乙胺基转移酶的研究进展[J].中国抗生素杂志,2006,31(6):335-338.
[2] LAMBALOT R H,GEHRING A M,FLUGEL R S,et al.A new enzyme superfamily-the phosphopante-theinyl transferases[J].Chem Biol,1996,3(11):923-936.
[3] SáNCHEZ C,DU L,EDWARDS D J,et al.Cloning and characterization of a phosphopantetheinyl transferase from Streptomyces verticillus ATCC15003,the producer of the hybrid peptide-polyketide antitumor drug bleomycin[J].Chem Biol,2001,8(7):725-738.
[4] NEVILLE C,MURPHY A,KAVANAGH K,et al.A 4′-phosphopantetheinyl transferase mediates non-pibosomal peptide synthetase activation in Aspergillus fumigatus[J].Chem Biochem-Eur J Chem Biol,2005,6(4):679-685.
[5] FINKING R,SOLSBACHER J,KONZ D,et al.Characterization of a new type of phosphopantetheinyl transferase for fatty acid and siderophore synthesis in Pseudomonas aeruginosa[J].J Biol Chem,2003,277(52):50293-50302.
[6] REUTER K,MOFID M R,MARAHIEL M A,et al.Crystal structure of the surfactin synthetase-activating enzyme Sfp:a prototype of the 4′-phosphopantetheinyl transferase superfamily[J].EMBO J,2000,18(23):6823-6831.
[7] LIU Q,MAY,ZHOU L,et al.Gene cloning,expression and functional characterization of a phosphopantetheinyl transferase from Vibrio anguillarum serotype O1[J].Arch Microbiol,2005,183(1):37-44.
[8] CHIRGADZE N Y,BRIGGS S L,McALLISTER K A,et al.Crystal structure of Streptococcus pneumoniae acyl carrier protein synthase:an essential enzyme in bacterial fatty acid biosynthesis[J].EMBO J,2000,19(20):5281-5287.
[9] PARRIS K D,LIN L,TAM A,et al.Crystal structures of substrate binding to Bacillus subtilis holo-(acyl carrier protein)synthase reveal a novel trimeric arrangement of molecules resulting in three active sites[J].Structure,2000,8(8):883-895.
[10] FICHTLSCHERER F,WELLEIN C,MITTAG M,et al.A novel function of yeast fatty acid synthase.Subunit alpha is capable of self-pantetheinylation[J].Eur J Biochem,2000,267(9):2666-2671.
[11] WEISSMAN K J,HONG H,OLIYNYK M,et al.Identification of a phosphopantetheinyl transferase for erythromycin biosynthesis in Saccharopolyspora erythraea[J].Cheminform,2004,5(1):116-125.
[12] FLUGEL R S,HWANGBO Y,LAMBALOT R H,et al.Holo-(acyl carrier protein) synthase and phosphopantetheinyl transfer in Escherichia coli[J].J Biol Chem,2000,275(2):959-968.
[13] McALLISTER K A,PEERY R B,MEIER T I,et al.Biochemical and molecular analyses of the Streptococcus pneumoniae acyl carrier protein synthase,an enzyme essential for fatty acid biosynthesis[J].J Biol Chem,2000,275(40):30864-30872.
[14] DEBABOV D V,HEATON M P,ZHANG Q,et al.The D-alanyl carrier protein in Lactobacillus casei:cloning,sequencing,and expression of dltC[J].J Bacteriol,1996,178(13):3869-3876.
[15] COX R J,HITCHMAN T S,BYROM K J,et al.Post-translational modification of heterologously expressed Streptomyces,type Ⅱ polyketide synthase acyl carrier proteins[J].FEBS Lett,1997,405(3):267-272.
[16] JOHNS A,SCHARF D H,GSALLER F,et al.A nonredundant phosphopantetheinyl transferase,PptA,Is a novel antifungal target that directs secondary metabolite,siderophore,and lysine biosynthesis in Aspergillus fumigatus and is critical for pathogenicity[J].MBio,2017,8(4):1504-1516.
[17] STUIBLE H P,MEIER S,WAGNER C,et al.A novel phosphopantetheine:protein transferase activating yeast mitochondrial acyl carrier protein[J].J Biol Chem,1998,273(35):22334-22339.
[18] CHU M,MIERZWA R,XU L,et al.Structure elucidation of Sch 538415,a novel acyl carrier protein synthase inhibitor from a microorganism[J].Bioorg Med Chem Lett,2003,13(21):3827-3829.
[19] GILBERT A M,KIRISITS M,TOY P,et al.Anthranilate 4H-oxazol-5-ones:novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors[J].Bioorg Med Chem Lett,2004,14(1):37-41.
[20] FOLEY T L,YOUNG B S,BURKART M D.Phosphopantetheinyl transferase inhibition and secondary metabolism[J].FEBS J,2009,276(23):7134-7141.
[21] KOSA N M,FOLEY T L,BURKART M D.Fluorescent techniques for discovery and characterization of phosphopantetheinyl transferase inhibitors[J].J Antibiot,2014,67(1):113-120.
[22] ALLEN G,BROMLEY M,KAYE S J,et al.Functional analysis of a mitochondrial phosphopantetheinyl transferase(PPTase)gene pptB,in Aspergillus fumigatus[J].Fungal Genet Biol,2011,48(4):456-464.
[23] KEATING D H,CAREY M R,CRONAN J E J.The unmodified (apo) form of Escherichia coli acyl carrier protein is a potent inhibitor of cell growth[J].J Biol Chem,1995,270(38):22229-22235.
[24] DOBB K S,KAYE S J,BECKMANN N,et al.Cha-racterisation of the Candida albicans phosphopante-theinyl transferase Ppt2 as a potential antifungal drug target[J/OL].PLoS One,2015,10(11):e0143770.
[25] VICKERY C R,KOSA N M,CASAVANT E P,et al.Structure,biochemistry,and inhibition of essential 4′-phosphopantetheinyl transferases from two species of mycobacteria[J].ACS Chem Biol,2011,9(9):1939-1944.
[26] FAWZI A B,MACDONALD D,BENBOW L L,et al.SCH-202676:an allosteric modulator of both agonist and antagonist binding to G protein-coupled receptors[J].Mol Pharmacol,2001,59 (1):30-37.
[27] RICE W G,SCHAEFFER C A,HARTEN B,et al.Inhibition of HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds[J].Nature,1993,361(6411):473-475.
[28] BIRCK M R,HOLLER T P,WOODARD R W.Identification of a slow tight-binding inhibitor of 3-deoxy-D-manno-octulosonic acid 8-phosphate synthase[J].Am Chem Soc,2000,122(122):9334-9335.
[29] PAYNE D J,GWYNN M N,HOLMES D J,et al.Drugs for bad bugs:confronting the challenges of antibacterial discovery[J].Nat Rev Drug Discov,2007,6(1):29-40.
[30] STEVENS Jr. W C,JONES R M,SUBRAMANIAN G,et al.Potent and selective indolomorphinan antagonists of the kappa-opioid receptor[J].J Med Chem,2000,43(14):2759-2769.
[31] AHMAD N,GUPTA S,HUSAIN M M,et al.Diffe-rential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells[J].Clin Cancer Res,2000,6(4):1524-1528.
[32] FOLEY T L,RAI G,YASGAR A,et al.4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide(ML267),a potent inhibitor of bacterial phosphopantetheinyl transferase that attenuates secondary metabolism and thwarts bacterial growth[J].J Med Chem,2014,57(3):1063-1078.
[33] LAMB A,KAPPOCK T J,SILVAGGI N R,et al.Breaking a pathogen′s iron will:inhibiting side-rophore production as an antimicrobial strategy[J].Biochim Biophys Acta,2015,1854 (8):1054-1070.
[2] LAMBALOT R H,GEHRING A M,FLUGEL R S,et al.A new enzyme superfamily-the phosphopante-theinyl transferases[J].Chem Biol,1996,3(11):923-936.
[3] SáNCHEZ C,DU L,EDWARDS D J,et al.Cloning and characterization of a phosphopantetheinyl transferase from Streptomyces verticillus ATCC15003,the producer of the hybrid peptide-polyketide antitumor drug bleomycin[J].Chem Biol,2001,8(7):725-738.
[4] NEVILLE C,MURPHY A,KAVANAGH K,et al.A 4′-phosphopantetheinyl transferase mediates non-pibosomal peptide synthetase activation in Aspergillus fumigatus[J].Chem Biochem-Eur J Chem Biol,2005,6(4):679-685.
[5] FINKING R,SOLSBACHER J,KONZ D,et al.Characterization of a new type of phosphopantetheinyl transferase for fatty acid and siderophore synthesis in Pseudomonas aeruginosa[J].J Biol Chem,2003,277(52):50293-50302.
[6] REUTER K,MOFID M R,MARAHIEL M A,et al.Crystal structure of the surfactin synthetase-activating enzyme Sfp:a prototype of the 4′-phosphopantetheinyl transferase superfamily[J].EMBO J,2000,18(23):6823-6831.
[7] LIU Q,MAY,ZHOU L,et al.Gene cloning,expression and functional characterization of a phosphopantetheinyl transferase from Vibrio anguillarum serotype O1[J].Arch Microbiol,2005,183(1):37-44.
[8] CHIRGADZE N Y,BRIGGS S L,McALLISTER K A,et al.Crystal structure of Streptococcus pneumoniae acyl carrier protein synthase:an essential enzyme in bacterial fatty acid biosynthesis[J].EMBO J,2000,19(20):5281-5287.
[9] PARRIS K D,LIN L,TAM A,et al.Crystal structures of substrate binding to Bacillus subtilis holo-(acyl carrier protein)synthase reveal a novel trimeric arrangement of molecules resulting in three active sites[J].Structure,2000,8(8):883-895.
[10] FICHTLSCHERER F,WELLEIN C,MITTAG M,et al.A novel function of yeast fatty acid synthase.Subunit alpha is capable of self-pantetheinylation[J].Eur J Biochem,2000,267(9):2666-2671.
[11] WEISSMAN K J,HONG H,OLIYNYK M,et al.Identification of a phosphopantetheinyl transferase for erythromycin biosynthesis in Saccharopolyspora erythraea[J].Cheminform,2004,5(1):116-125.
[12] FLUGEL R S,HWANGBO Y,LAMBALOT R H,et al.Holo-(acyl carrier protein) synthase and phosphopantetheinyl transfer in Escherichia coli[J].J Biol Chem,2000,275(2):959-968.
[13] McALLISTER K A,PEERY R B,MEIER T I,et al.Biochemical and molecular analyses of the Streptococcus pneumoniae acyl carrier protein synthase,an enzyme essential for fatty acid biosynthesis[J].J Biol Chem,2000,275(40):30864-30872.
[14] DEBABOV D V,HEATON M P,ZHANG Q,et al.The D-alanyl carrier protein in Lactobacillus casei:cloning,sequencing,and expression of dltC[J].J Bacteriol,1996,178(13):3869-3876.
[15] COX R J,HITCHMAN T S,BYROM K J,et al.Post-translational modification of heterologously expressed Streptomyces,type Ⅱ polyketide synthase acyl carrier proteins[J].FEBS Lett,1997,405(3):267-272.
[16] JOHNS A,SCHARF D H,GSALLER F,et al.A nonredundant phosphopantetheinyl transferase,PptA,Is a novel antifungal target that directs secondary metabolite,siderophore,and lysine biosynthesis in Aspergillus fumigatus and is critical for pathogenicity[J].MBio,2017,8(4):1504-1516.
[17] STUIBLE H P,MEIER S,WAGNER C,et al.A novel phosphopantetheine:protein transferase activating yeast mitochondrial acyl carrier protein[J].J Biol Chem,1998,273(35):22334-22339.
[18] CHU M,MIERZWA R,XU L,et al.Structure elucidation of Sch 538415,a novel acyl carrier protein synthase inhibitor from a microorganism[J].Bioorg Med Chem Lett,2003,13(21):3827-3829.
[19] GILBERT A M,KIRISITS M,TOY P,et al.Anthranilate 4H-oxazol-5-ones:novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors[J].Bioorg Med Chem Lett,2004,14(1):37-41.
[20] FOLEY T L,YOUNG B S,BURKART M D.Phosphopantetheinyl transferase inhibition and secondary metabolism[J].FEBS J,2009,276(23):7134-7141.
[21] KOSA N M,FOLEY T L,BURKART M D.Fluorescent techniques for discovery and characterization of phosphopantetheinyl transferase inhibitors[J].J Antibiot,2014,67(1):113-120.
[22] ALLEN G,BROMLEY M,KAYE S J,et al.Functional analysis of a mitochondrial phosphopantetheinyl transferase(PPTase)gene pptB,in Aspergillus fumigatus[J].Fungal Genet Biol,2011,48(4):456-464.
[23] KEATING D H,CAREY M R,CRONAN J E J.The unmodified (apo) form of Escherichia coli acyl carrier protein is a potent inhibitor of cell growth[J].J Biol Chem,1995,270(38):22229-22235.
[24] DOBB K S,KAYE S J,BECKMANN N,et al.Cha-racterisation of the Candida albicans phosphopante-theinyl transferase Ppt2 as a potential antifungal drug target[J/OL].PLoS One,2015,10(11):e0143770.
[25] VICKERY C R,KOSA N M,CASAVANT E P,et al.Structure,biochemistry,and inhibition of essential 4′-phosphopantetheinyl transferases from two species of mycobacteria[J].ACS Chem Biol,2011,9(9):1939-1944.
[26] FAWZI A B,MACDONALD D,BENBOW L L,et al.SCH-202676:an allosteric modulator of both agonist and antagonist binding to G protein-coupled receptors[J].Mol Pharmacol,2001,59 (1):30-37.
[27] RICE W G,SCHAEFFER C A,HARTEN B,et al.Inhibition of HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds[J].Nature,1993,361(6411):473-475.
[28] BIRCK M R,HOLLER T P,WOODARD R W.Identification of a slow tight-binding inhibitor of 3-deoxy-D-manno-octulosonic acid 8-phosphate synthase[J].Am Chem Soc,2000,122(122):9334-9335.
[29] PAYNE D J,GWYNN M N,HOLMES D J,et al.Drugs for bad bugs:confronting the challenges of antibacterial discovery[J].Nat Rev Drug Discov,2007,6(1):29-40.
[30] STEVENS Jr. W C,JONES R M,SUBRAMANIAN G,et al.Potent and selective indolomorphinan antagonists of the kappa-opioid receptor[J].J Med Chem,2000,43(14):2759-2769.
[31] AHMAD N,GUPTA S,HUSAIN M M,et al.Diffe-rential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells[J].Clin Cancer Res,2000,6(4):1524-1528.
[32] FOLEY T L,RAI G,YASGAR A,et al.4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide(ML267),a potent inhibitor of bacterial phosphopantetheinyl transferase that attenuates secondary metabolism and thwarts bacterial growth[J].J Med Chem,2014,57(3):1063-1078.
[33] LAMB A,KAPPOCK T J,SILVAGGI N R,et al.Breaking a pathogen′s iron will:inhibiting side-rophore production as an antimicrobial strategy[J].Biochim Biophys Acta,2015,1854 (8):1054-1070.