User:Benjah-bmm27/degree/3/RJC

=Natural products, RJC=
 * Natural products

Examples of natural products

 * Fluoroacetate
 * Penicillin G – a nonribosomal peptide
 * Caffeine – an alkaloid
 * Cocaine – alkaloid
 * Erythromycin A – a polyketide
 * Lanosterol – a terpene
 * Tenellin – nonribosomal peptide
 * Brevetoxin A1 – polyketide


 * Biosynthesis

Origin of natural products: secondary metabolism

 * Primary metabolism
 * Photosynthesis: CO2 → glucose
 * Glycolysis: glucose → phosphoenolpyruvic acid → acetyl CoA
 * Citric acid cycle: acetyl CoA ↔ citric acid → aliphatic amino acids


 * Secondary metabolism: alkaloids, polyketides, terpenes and nonribosomal peptides

Biological methylation

 * S-adenosylmethionine – biological equivalent of methylating agents like methyl iodide

Non-ribosomal peptide biosynthesis

 * Thioesterases (TE) release acyl groups bound to enzymes as thioesters by simple hydrolysis
 * Enz-S-C(=O)-R + H2O –[TE]→ Enz-SH + RCO2H

Lovastatin biosynthesis

 * Lovastatin

Terpene biosynthesis

 * Mevalonic acid pathway
 * Acetyl CoA + acetoacetyl CoA → HMG-CoA → mevalonic acid → phosphomevalonic acid → diphosphomevalonic acid → isopentenyl pyrophosphate (IPP) → dimethylallyl pyrophosphate (DMAPP)
 * Steroid biosynthesis
 * DMAPP + IPP → geranyl pyrophosphate (GPP) → farnesyl pyrophosphate → squalene → lanosterol
 * Monoterpene biosynthesis
 * GPP → linalool or limonene or α-pinene or β-pinene via carbocations
 * GPP →→ fenchone
 * Diterpene biosynthesis
 * geranylgeranyl pyrophosphate → ent-copalyl pyrophosphate → ent-kaurene →→ gibberellin A3
 * Triterpene biosynthesis
 * Squalene → squalene epoxide →→ lanosterol
 * Oxidative demethylation
 * Dihydrolanosterol → alcohol → aldehyde → formyl ester →→ cholesterol
 * Cholesterol →→ progesterone → androstendione → testosterone
 * Human aromatase
 * Androstendione →→ estrone → estradiol → estriol

Alkaloid biosynthesis
Alkaloids all contain a basic nitrogen atom. Their names end in -ine.

Examples of alkaloids

 * Morphine
 * Heroin
 * Codeine
 * Lysergic acid
 * Caffeine
 * Coniine
 * Strychnine
 * Aconitine
 * Nicotine
 * Epibatidine
 * Cocaine

Morphine biosynthesis

 * (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

 * 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

 * 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