天然药物化学第二讲.ppt

1、Introduction to the Studies of Biosynthesis of Natural Products,Yuemao S,College of Pharmaceutical Sciences,Shandong UniversitySeptember 13,2010,3.Three examples,The Biosynthesis of Taxol,Techniques we applied:A.Stable isotope labeling,feedingB.Radioactive isotope tracing in Enzymatic acetylation Co

2、nclusion:10-deacetylbaccatin-III is a precursor of taxol,Hypothetic multiple pathways towards taxol,The biosynthesis of rifamycin B,Two possible pathways,A and B,towards rifamycin B.A demanded that protorifamycin I is the key intermediate and the oxygen at the C-8 position is introduced later.B requ

3、ired that the oxygen at C-8 is of the same origin as the carbon of C-8,i.e.,from the carboxyl group of AHBA.,Methods and Techiques:DNA mutagensis;stable isotope labeling,feeding;13C NMR assay;LC-ESI-MSConclusions:A.The C-8 oxygen is the same origin as the C-8 carbonB.The formation of naphthoquinone

4、precedes the lactamizationC.The biosynthesis of type I polyketides occurs progressively,The sequence of the formation of the naphthoquinone and lactam,The biosynthesis of Streptomyces spore pigment,Origins of Building Blocks,Common Building Blocks,C1,C2,C5,Common Building Blocks,C6C3,C6C2,C6C1,C6C2N

5、,Common Building Blocks,C4N,C5N,Indole-C2N,Common FAs,Acyl Thioester,General Chemistry,Aldol and Claisen Condensation,Aldol and Claisen Condensation,Aldol and Claisen Condensation,Malonyl CoA:activated acetyl CoA,Malonyl CoA:activated acetyl CoA,Overall Biosynthetic Scheme,Bacterial Aromatic Polyket

6、ides,Bacterial Aromatic Polyketides,Bacterial Aromatic Polyketides,Bacterial Reduced Polyketides,A,Acetate;P,Propionate;B,Butyrate;G,Glycerol;S,Starter from branched chain or cyclic units,Bacterial Reduced Polyketides,Bacterial Reduced Polyketides,Fungal Aromatic Polyketides(Non-reduced/Partially Re

7、duced Polyketides),Orsellinic acid,Tetrahydroxynaphthalene(THN),6-Methylsalicylic acid(MSA),Norsolorinic acid,Fungal Aromatic Polyketideswith unusual features-mixed reduced/non-reduced,Unusual acetate labelUnusual starterUnusual mix,Fungal Highly Reduced Polyketides,T-toxin,Mevacor,Statins,hydroxy-m

8、ethylglutaryl-CoA(HMG-CoA).,Fungal Aromatic Polyketides(Non-reduced/Partially Reduced Polyketides),Orsellinic acid,Tetrahydroxynaphthalene(THN),6-Methylsalicylic acid(MSA),Norsolorinic acid,Plant Polyketides(Bacterial polyketides made by the same type of PKS),chalcone in higher plants,1,3,6,8-tetrah

9、ydroxynaphthalene(THN)in Streptomyces griseus and S.coelicolor,3,5-dihydroxyphenylacetic acid(DHPA)in Amycolatopsis mediterranei and A.orientalis,Plant Polyketides(Starter:Phenylpropanhoid Pathway),chalcone,Plant Polyketides(Bacterial polyketides made by the same type of PKS),chalcone in higher plan

10、ts,1,3,6,8-tetrahydroxynaphthalene(THN)in Streptomyces griseus and S.coelicolor,3,5-dihydroxyphenylacetic acid(DHPA)in Amycolatopsis mediterranei and A.orientalis,Nonribosomal Peptides,Antibiotics,Nonribosomal Peptides,Antibiotics,Nonribosomal Peptides,Immunosuppresants,Nonribosomal Peptides,Toxins,

11、Nonribosomal Peptides,Nonribosomal Peptides,Nonribosomal Peptides,Nonribosomal Peptides,Nonribosomal Peptides,Nonribosomal Peptides,Antibiotics,Nonribosomal Peptides,Antibiotics,Nonribosomal Peptides,Last resort for against drug-resistant pathogens,Nonribosomal Peptides,Hybrid NRP-PK,Nonribosomal Peptides,Hybrid NRP-PK-C-aminated,Nonribosomal Peptides,Hybrid NRP-PK-N-acylated,Nonribosomal Peptides,