User:Benjah-bmm27/degree/3/RJC
Appearance
Natural products, RJC
[edit]Examples of natural products
[edit]- Fluoroacetate
- Penicillin G – a nonribosomal peptide
- Caffeine – an alkaloid
- Cocaine – alkaloid
- Erythromycin A – a polyketide
- Lanosterol – a terpene
- Tenellin – nonribosomal peptide
- Brevetoxin A1 – polyketide
Origin of natural products: secondary metabolism
[edit]- Primary metabolism
- Photosynthesis: CO2 → glucose
- Glycolysis: glucose → phosphoenolpyruvic acid → acetyl CoA
- Citric acid cycle: acetyl CoA ↔ citric acid → aliphatic amino acids
Themes
[edit]Biological methylation
[edit]- S-adenosylmethionine – biological equivalent of methylating agents like methyl iodide
Examples of key experiments in biosynthesis
[edit]Radiolabelling
[edit]Non-ribosomal peptide biosynthesis
[edit]- Thioesterases (TE) release acyl groups bound to enzymes as thioesters by simple hydrolysis
- Enz-S-C(=O)-R + H2O –[TE]→ Enz-SH + RCO2H
Polyketide biosynthesis
[edit]Lovastatin biosynthesis
[edit]Terpene biosynthesis
[edit]- Mevalonic acid pathway
- Steroid biosynthesis
- DMAPP + IPP → geranyl pyrophosphate (GPP) → farnesyl pyrophosphate → squalene → lanosterol
- Monoterpene biosynthesis
- Diterpene biosynthesis
- Triterpene biosynthesis
- Squalene → squalene epoxide →→ lanosterol
- Oxidative demethylation
- Dihydrolanosterol → alcohol → aldehyde → formyl ester →→ cholesterol
- Cholesterol →→ progesterone → androstendione → testosterone
- Human aromatase
Alkaloid biosynthesis
[edit]Alkaloids all contain a basic nitrogen atom. Their names end in -ine.
Examples of alkaloids
[edit]- Morphine
- Heroin
- Codeine
- Lysergic acid
- Caffeine
- Coniine
- Strychnine
- Aconitine
- Nicotine
- Epibatidine
- Cocaine
Morphine biosynthesis
[edit]- (S)-norcoclaurine from tyrosine
- Tyrosine –[decarboxylase, PLP, −CO2]→ tyramine –[O]→ dopamine
- Tyrosine –[ aminotransferase, PLP]→ 4-hydroxyphenylpyruvic acid –[ −CO2 ]→ 4-hydroxyphenylacetaldehyde
- Dopamine + 4-hydroxyphenylacetaldehyde –[ (S)-norcoclaurine synthase ]→ (S)-norcoclaurine (a Pictet-Spengler reaction)
- (R)-reticuline from (S)-norcoclaurine
- (S)-norcoclaurine –[O-methyl transferase, SAM]→ methoxy –[N-methyl transferase, SAM]→ N-methyl –[O]→ benzenediol –[O-Me Tf, SAM]→ (S)-reticuline
- (S)-reticuline –[O]→ iminium –[NADPH]→ (R)-reticuline
- Morphine from (R)-norcoclaurine
- (R)-reticuline –[P450, O, remove 2H]→ salutaridine (radical mechanism)
- salutaridine –[NADPH]→ salutaridinol → thebaine
- thebaine –[oxidative demethylation then rearrangement]→ codeinone
- codeinone –[NADPH]→ –[oxidative demethylation]→ morphine
Pictet-Spenglerase
[edit]- Strictosidine synthase
- Tryptamine + secologanin (a monoterpene) → strictosidine
- O'Connor et al, J. Am. Chem. Soc. (2008) 130, 710–723
- Strictosidine is a precursor for many natural products, some useful as medicines
- Vinblastine (cancer)
- Yohimbine (sexual disorders)
- Ajmaline (arrhythmia)
- Camptothecin (cancer)
- Strychnine (toxin)
Cocaine biosynthesis
[edit]- Biosynthesis of cocaine
- Ornithine –[decarboxylase, PLP]→ putrescine –[SAM]→ N-methylputrescine –[aminotransferase, PLP]→ aldehyde –[intramolecular imine formation]→ N-methylpyrrolinium ion
- N-methylpyrrolinium –[acetyl CoA as C-nucleophile]→ an acetyl pyrrolidine –[acetyl CoA]→ a malonyl pyrrolidine –[P450]→ hydroxylated pyrrolidine –[H+, −H2O]→ a malonyl pyrrolinium ion –[intramolecular Mannich rxn]→→ methylecgonine –[ benzoyl CoA ]→ cocaine