Download 1b. Loss of N

Review of organic mechanisms used in construction of 2o metabolites
I. Reactions used in building and modifying carbon skeletons
1. Alkylations using SAM to produce a methoxy, N-methyl or methyl group
2 examples of how C becomes nucleophilic and forms
bond with CH3 group:
2. Prenylations: Addition of an isoprene group
Ex: C-alkylation with DMAPP
Vit K skeletons
3. C-C bond formation through electrophilic addition
Assembly of building blocks and cyclization requires generation of a carbocation
center that reacts with nearby pi electrons
Gain and loss of a carbocation can occur in different ways
4. Rearrangements: once the pieces are put together, parts may migrate due to
hydride and alkyl shifts:
Example: Skeletons of terpenes like these volatiles and
essential oils vary greatly in structure due to rearrangements
Precursor to cholesterol is formed from squalene through cyclizations and shifts
5. Aldol & Claisen condensations often occur to facilitate C-C
bond formation when reactants are carbonyl compounds
Claisen condensation of thioesters is used in chain-building: malonyl CoA + acetyl CoA
are condensed to form a 4 C unit in the acetate pathway
Another example: aldol-type condensations are used to assemble a ring
from PEP and D-E-4-P at the beginning of the shikimate pathway
6. C-C bond formation through Mannich reaction:
Iminium nitrogen activates the imine C towards nucleophilic attack
Example: cyclization to
form a tropane ring structure
7. Phenolic oxidative coupling:
Formation of radicals happens readily with phenols, enabling two aromatic rings
to attach through homolytic bond formation
8. Glycosylation: nature’s way of increasing water-solubility by attaching one or
more sugars to the organic part or “aglycone” moiety to an organic product
Example: quercetin-3-galactoside, and other glycosides of quercetin are
found in fruit and leaves of cranberry
Quercetin is a flavonol
Antioxidant with mild anti-tumor activity
it also may protect the plant from pests
galactose or
other sugars
Digitoxin a “cardiac glycoside”
from foxglove, Digitalis purpurea
Digitoxin competes with K+ for a binding site on enzyme
potassium-ATPase (potassium blocker/antagonist) inhibiting
Na-K ATPase pump. By blocking this activity, it causes Ca2+ to
be transported out more slowly; so heart muscle is exposed to
Ca2+ for a longer period of time. As a result, the heart contracts
more forcefully (“inotropic effect”) It also increases cholinergic
stimulation to the heart, which slows it down (steadier,
stronger heartbeat with more rest between beats) Too high a
dose of Digitalis can be toxic, but the therapeutic dose is about
50% of the toxic dose so it must be taken with care. Similar
compounds have been used as arrow poisons!
9. Decarboxylations
Loss of COOH group
as CO2 occurs in
amino acids and
other acids
Often assisted by
coenzymes or
cofactors (Vit B6 & B1)
II. Mechanisms of functional group transformation
1. Gain or loss of N
Often occurs through formation or hydrolysis of imine (Schiff base)
1a. Amination reactions: Gain of N by a molecule
Reductive amination: N comes from ammonia
Transamination: NH2 group is transferred from an amino acid
1b. Loss of N:
Deamination of
an amino acid
by Vitamin B6
involves imine
formation and
hydrolysis
2. Gain or loss of bonds to oxygen: Oxidations and Reductions
Catalyzed by enzymes together with cofactors
NAD+/NADP+ (works with dehydrogenases)
--Oxidation of hydroxyl group to carbonyl or aldehyde to carboxylic acid
--Oxidation of amine to imine
NADH/NADPH
--Reduction of carbonyls to alcohols
--Reduction of oxygen in reactions with substrates that gain a single O:
2a. Mono-oxygenases catalyze the addition of a single O atom from O2
to the substrate (substrate is oxidized),
The role of NADH is to reduce the second oxygen to form water (next slide)
+ H2O
Some monooxygenases are
cytochrome P-450-dependent
(e.g. hydroxylases, important in
detoxification, drug metabolism)
Produce alcohols & phenols
Aromatic hydroxylation involves
formation of epoxide intermediate
CYP450 dependent monooxygenases can also form methylenedioxy bridges
(ex: podophyllotoxin, Fig. 2.3
antimitotic)
2b.
Dioxygenases catalyze
oxidative cleavage
reactions of C=C
yielding ketones,
aldehydes or acids
Common with alkenes
Even aromatic C=C can
be cleaved this way...pi
bonds adjacent to OH
are particularly reactive
2c. Oxidases & peroxidases
catalyze carbonyl formation.
Substrate OH group loses H,
and oxygen or H2O2 acts as
acceptor
Example: Oxidation of phenols
to quinones
2d. Amine oxidases swap nitrogen
for an oxygen, usually transform
amines to aldehydes
Key role of MAO: breakdown of
neurotransmitters in the brain
(serotonin, epinephrine, etc)…too
much MAO can cause depression,
thus MAO inhibitors are a class of
anti-depressant