CNGNGE JOHN MCMURRY CHAPTER 25 Secondary Metabolites: An Introduction to Natural Products Chemistry T H I R D EDITION Organic Chemistry with Biological Applications
CHAPTER 25 Secondary Metabolites: An Introduction to Natural Products Chemistry
Secondary Metabolites:An Introduction to Natural Products Chemistry Natural products generally refer to secondary metabolites Small molecules that are HO essential to the growth CO2H and development of the producing organism CH Not classified by structureHo H OH H OH Over 300,000 secondary Morphine Prostaglandin E1 metabolites exist H3C OH OH H3C、 CH3 OH N(CH3)2 CH3 CH3 OCH3 CH3 _oh CH3 Erythromycin A Benzylpenicillin
Natural products generally refer to secondary metabolites ▪ Small molecules that are essential to the growth and development of the producing organism ▪ Not classified by structure ▪ Over 300,000 secondary metabolites exist Secondary Metabolites: An Introduction to Natural Products Chemistry
25-1 Classification of Natural Products Natural products are generally grouped into five main classes Natural Products (secondary metabolites) Terpenoids, Alkaloids Fatty acids, Steroids Polyketides Nonribosomal Enzyme polypeptides cofactors
Natural products are generally grouped into five main classes 25-1 Classification of Natural Products
Classification of Natural Products Terpenoids and steroids Over 35,000 known Derived biosynthetically from isopentenyl diphosphate Terpenoids exhibit an immense variety of structures Steroids have a common tetracyclic carbon skeleton that are biosynthesized from triterpene lanosterol
Terpenoids and steroids ▪ Over 35,000 known ▪ Derived biosynthetically from isopentenyl diphosphate ▪ Terpenoids exhibit an immense variety of structures ▪ Steroids have a common tetracyclic carbon skeleton that are biosynthesized from triterpene lanosterol Classification of Natural Products
Classification of Natural Products Alkaloids More than 12,000 known Contain a basic amine group Derived biosynthetically from amino acids
Alkaloids ▪ More than 12,000 known ▪ Contain a basic amine group ▪ Derived biosynthetically from amino acids Classification of Natural Products
Classification of Natural Products Fatty acid-derived substances and polyketides More than 10,000 known Biosynthesized from simple acyl precursors such as acetyl CoA,propionyl CoA,and methylmalonyl CoA Natural products derived from fatty acids,such as prostaglandin E1,generally have most of the oxygen atoms removed Polyketides,such as the antibiotic erythromycin,often have many oxygen substituents remaining
Fatty acid-derived substances and polyketides ▪ More than 10,000 known ▪ Biosynthesized from simple acyl precursors such as acetyl CoA, propionyl CoA, and methylmalonyl CoA ▪ Natural products derived from fatty acids, such as prostaglandin E1 , generally have most of the oxygen atoms removed ▪ Polyketides, such as the antibiotic erythromycin, often have many oxygen substituents remaining Classification of Natural Products
Classification of Natural Products Nonribosomal polypeptides Peptidelike compounds Biosynthesized from amino acids by a multifunctional enzyme complex without direct RNA transcription,such as penicillins Enzyme cofactors Coenzymes such as pyridoxal phosphate(PLP)
Nonribosomal polypeptides ▪ Peptidelike compounds ▪ Biosynthesized from amino acids by a multifunctional enzyme complex without direct RNA transcription, such as penicillins Enzyme cofactors ▪ Coenzymes such as pyridoxal phosphate (PLP) Classification of Natural Products
25-2 Biosynthesis of Pyridoxal Phosphate 0 -0 00 Figure 25.1 一OH H 一OH C=0 一OH 0 一OH H -OH 3 H -OH Pathway for pyridoxal 5'- CH20P032 CH20P032 CH20P032 CH20P032 phosphate biosynthesis D-Erythronate 3-Hydroxy-4-phospho- 4-Phospho- 4-phosphate hydroxy-2-ketobutyrate hydroxythreonine CH3 CH3 Pyruvate =0 co. =0 HO- H 0P033 OH 0 H CH20P032 1-Amino-3-hydroxy- D-Glyceraldehyde acetone 3-phosphate 3-phosphate -OH 1-Deoxyxylulose CH2OPO32- 5-phosphate 6 CH20P032 CH2OH Pyridoxine 5'-phosphate OH CH3 0 CH2OPO32 CHO Pyridoxal 5'-phosphate(PLP) OH
Figure 25.1 Pathway for pyridoxal 5′- phosphate biosynthesis 25-2Biosynthesis of Pyridoxal Phosphate
Biosynthesis of Pyridoxal Phosphate STEPS 1-2 OF FIGURE 25.1:OXIDATION Biosynthesis of pyridoxal phosphate begins with oxidation of aldehyde group in D-erythrose 4-phosphate to give D- erythronate 4-phosphate Requires NAD+as cofactor Cysteine-SH group in enzyme adds to aldehyde carbonyl group of D-erythrose 4-phosphate to give intermediate hemithioacetal Hemithioacetal is oxidized by NAD+to a thioester Hydrolysis of thioester yields erythronate 4-phosphate
STEPS 1-2 OF FIGURE 25.1: OXIDATION Biosynthesis of pyridoxal phosphate begins with oxidation of aldehyde group in D-erythrose 4-phosphate to give Derythronate 4-phosphate ▪ Requires NAD+ as cofactor ▪ Cysteine –SH group in enzyme adds to aldehyde carbonyl group of D-erythrose 4-phosphate to give intermediate hemithioacetal ▪ Hemithioacetal is oxidized by NAD+ to a thioester ▪ Hydrolysis of thioester yields erythronate 4-phosphate Biosynthesis of Pyridoxal Phosphate
Biosynthesis of Pyridoxal Phosphate Oxidation of thioester-OH group at C2 by NAD+gives 3- hydroxy-4-phosphohydroxy-2-ketobutyrate NAD+ Enz Enz CONH2 -H NADH/H+ H20 En2SH OH OH H OH -OH H -OH OH CH20P032 CH20P032 CH20P032 D-Erythrose Hemithioacetal Thioester 4-phosphate 0c0 NAD+ NADH/H+ H OH C=0 H -OH H -OH CH20P032 CH2OPO32- D-Erythronate 3-Hydroxy-4-phospho- 4-phosphate hydroxy-2-ketobutyrate
▪ Oxidation of thioester –OH group at C2 by NAD+ gives 3- hydroxy-4-phosphohydroxy-2-ketobutyrate Biosynthesis of Pyridoxal Phosphate