Major Classes of Natural Products 2 Flashcards
What are the building blocks of natural product peptides?
proteinogenic and non-proteinogenic amino acids
Where have they been isolated from?
from a range of organisms (fungi, bacteria, sponges, etc.)
Biosynthetic routes to make peptide natural products?
there are different type of biosynthetic routes to make peptide natural products
Building blocks of Non-ribosomal peptides, and examples?
building blocks: amino acids
penicillin G, tyrocidine A, cyclosporin A, cycloaspeptide A, cycloaspeptide E
NRP - biosynthesis overview
synthase/synthase gene (backbone)
- non-ribosomal peptide synthetase (NRPS) + amino acids
what are NRP synthesised by?
non-ribosomal peptide synthetases (NRPS)
what are NRPSs?
megasynthetases - they have catalytic domains
independent or dependent of mRNA?
independent of mRNA
NRP Biosynthesis
are they modular or iterative?
modular (bacteria and fungi), there are some iterative examples (not covered here)
What do they need to activate the building block?
ATP
synthetase vs polyketide synthase?
synthetase uses ATP
polyketide synthase does not use ATP
NRPS Biosynthesis
Function of the domains (steps 1-4)
- activation and loading
- initiation
- elongation
- termination
NRPS Biosynthesis
1. activation and loading
Adenylation (A) domain will select and activate with ATP a specific amino acid
NRPS Biosynthesis
2. initiation
the first two amino acids will be joined together by the condensation (C) domain
NRPS Biosynthesis
3. Elongation
the remaining of amino acids are joined together
depends on how many extra modules we have
by condensation domains
NRPS Biosynthesis
4. Termination
peptide is released by the thioesterase (TE) domain or a terminal Condensation domain (CT) (small T at the bottom)
one module =
one amino acid
what are the 4 core domains?
C, A, PCP, TE
Condensation, Adenylation, PCP, TE/CT (small T, at the bottom)
NRPS Biosynthesis - penicillin
Further modifications:
additional domains and tailoring genes?
additional domains:
- Epimerase (E)
- N-methyl transferase (NMeT)
tailoring genes
- e.g. oxidation for ring formation, Acyl transferase
if a domain = three =
tripeptide
NRPS Biosynthesis - Cyclosporin
further modifications:
additional domains and tailoring genes?
additional domains:
- Epimerase (E)
- N-methyl transferase (NMeT)
tailoring genes:
- e.g. Methyl transferase
Yang et al. (2018)
NRPS Biosynthesis - Cyclosporin
1. produced by?
2. discovered in?
3. has what activities?
4. also used as an?
5. what does it prevent?
6. WHO?
- Tolypocladium inflatum
- 1971
- cyclosporin has antifungal activity
- used as an immunosuppressant drug
- prevent organ transplant rejection
- WHO - essential medicines
How to recognise a NRPS-derived SM?
- always have CHON as elements
- can have halogen (Br, Cl, etc.)
- similar number of nitrogen oxygens atoms
- amides bonds are present
- amino acid side chains
NPs - Terpenes
Examples?
- Menthol
- B-carotene
- Pleuromutilin
- Botrydial
- Artemisinin
Terpene biosynthesis overview
Synthase/synthetase gene (backbone)
-> Terpene synthase + IPP
Terpene Biosynthesis
1. what are the building blocks?
2. isolated from?
3. how many carbon units each do two building units have?
4. synthesised by?
5. what can be added?
6. what are the different classes based on?
7. difference between terpenoids and terpenes
- isopentyl pyrophosphates (IPP) and dimethylallyl pyrophosphate (DMAPP)
- from a range of organisms (fungi, bacteria, sponges, plants and animals)
- the two building units have 5 carbon units each (terpenes dividable by 5 carbons)
- synthesised by a terpene synthase that joins the two units together
- IPP can be added adding additional IPP units
- different classes based on the length
- terpenoids are terpenes with additional functional groups like (-OH)
terpene = carbon, hydrogen in structure
terpenoids = carbon, hydrogen, oxygen in structure
Terpene Biosynthesis - pleuromutilin
1. produced by?
2. how many carbons does core structure have?
3. what activities?
4. what are its derivatives used in?
5. active against?
- Basidiomycota - Clitopilus passeckerianus
- 20 carbons
- antibiotic activity
- its derivatives are used in veterinary (used for swine (pigs) specifically) and human medicine
- active against Gram-negative bacteria
Terpene Biosynthesis - artemisin
1. produced by?
2. how many carbons does the core structure have?
3. traditional medicine?
4. type of drug it is used for?
5. Nobel Prize in Medicine - who, what year, and what for?
6. market and lives saved?
7. how is the final step catalysed?
- Artemisia annua (sweet wormwood)
- core structure has 15 carbons
- Traditional Chinese medicine (317-420 AD)
- Antimalarial drug
- Tu Youyou, 2015, for the discovery
- Market $597.2M (2023) - over 200 M lives saved
- final step catalysed by UV light and oxygen
Reed et al. (2023)
Terpene Biosynthesis - saponins
1. produced by?
2. extracted from?
3. used in?
4. also used for?
- plants terpenoids
- soapbark tree (Quillaja Saponaria)
- formulation of soaps, medicines, root beer foam, etc.
- adjuvants (substances that increase the effectiveness of drugs or vaccines) - immunostimulatory activity to vaccines (shingles, malaria, and COVID-19)
How to recognise a terpene-derived SM?
- the molecular formular has CH (terpenes) and CHO (terpenoids) as elements
- main carbon skeleton should feature 5 or multiple of 5 carbons
- common to alkenes and rings
Examples of terpenes (including whether they are terpene or terpenoid)?
- Menthol = terpenoid
- B-carotene = terpene
- Pleuromutilin = terpenoid
- Botrydial = terpenoid
- Artemisinin = terpenoid
Main classes - summary
Synthase/synthetase gene (backbone)
-> Polyketide - Polyketide synthase (PKS) + Acyl CoA
-> Non-ribosomal peptides - Non-ribosomal peptide synthetase (NRPS) + amino acids
-> Terpenes/terpenoids - Terpene synthase + IPP
PKS and NRPS can be modular & iterative
