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

Themes

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

Polyketide biosynthesis

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