CHEM 230

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Organic Chemistry Notes:
Glycolysis: converting glucose into pyruvate
Step 1: Phosphorylation of Glucose
pentaintermediate that kicks off ATP
Glucose OH group is pointed down
Step 2: Isomerization
keto-enol tautomerization
Step 3: Phosphorylation of Fructose-6-Phosphate
note that the version of Fructose-6-phosphate is phosphorylated
Glucose in equilibrium with Glucose
Step 4: Cleavage
think Imine Schiff in beginning
followed by retro aldol
Step 5: Isomerization
again, keto-enol tautomerization
Steps 6 and 7: Oxidation/Phosphorylation
phosphate attacks just like a nucleophile
in effect: conversion of aldehyde into a carboxylic acid
reaction of 1,3-biphosphoglycerate with ADP
transfer of phosphoryl group to yield ATP (ADP just attacks like a nucleophile)
Step 8: Isomerization
catalyzed by phosphoglycerate mutase
moving phosphate up one carbon (from last to middle carbon)
first attack by middle oxygen, then bottom phosphate gets attacked and you end up with
alcohol on the bottom
Step 9: Dehydration
thought to be an E1cB process, that ends up kicking off OH
Step 10: Transfer of Phosphoryl Group to ADP
generates ATP and gives enolpyruvate
enolpyruvate undergoes tautomerization to pyruvate
**two equivalents of Mg2+ (one to ADP, one to increase acidity of water molecule for
enolate ion protonation)
again ADP just attacks phosphorous like a nucleophile





Transformations of Pyruvate
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Conversion of Pyruvate to Lactate:
NADH reduces pyruvate with concurrent protonation leads to S-lactate (alcohol)
just leads to alcohol
Conversion of Pyruvate to Ethanol:
Step 1: Addition of TPP
Thiamin diphosphate (TPP) ylid does nucleophilic addition to ketone to yield an alcohol
addition product
Step 2: Decarboxylation
addition product undergoes decarboxylation, pushing electrons into the electron sink
(N+)
Step 3-4: Protonation and TPP Elimination
Nitrogen kicks down electrons again and the double bond is protonated
OH is deprotonated to give the elimination of TPP ylid and you end up with an aldehyde
aldehyde is then reduced by alcohol dehydrogenase to give ethanol
NADH used as a cofactor (pro-R hydrogen in NADH transferred to re face)
Conversion of Pyruvate to Acetyl CoA:
multistep sequence catalyzed by complex of three enzymes and cofactors -- the pyruvate
dehydrogenase complex
Steps 1,2: TPP addition and decarboxylation
same as above, ending with HETPP
Step 3: Enamine Double Bond attacks Lipoamide Sulfur
nitrogen lone pair kicks down, double bond attacks to open Lipoamide ring
S
N
2 like displacement
Step 4: Elimination of TPP
induced by abstraction of H from OH
Step 5: Nucleophilic acyl substitution reaction with coenzyme A
just replace the weird chain with SCoA
COASH is the carrier
(Dihydrolipoamide is returned to Lipoamide see page 184)
nonoxidative: simple protonation; no oxygen involved
oxidative: thioester, oxygen involved







The Citric Acid Cycle:
overall result: conversion of an acetyl group into two molecules of CO
2
plus reduced
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coenzymes
requires NAD
+
and FAD to be constantly available, which means that NADH AND
FADH
2
must be reoxidized via the electron transport chain
this requires oxygen to be the electron acceptor
relies on oxygen as the electron acceptor and the operation of the electron transport chain


Step 1: Acetyl CoA adds to oxaloacetate
first proton is abstracted, then an alcohol is generated
the alcohol is deprotonated and the C=C bond is the nucleophile
end product: alcohol
H
2
O is deprotonated then substitutes out SCoA
Step 2: Isomerization
acidic hydrogen is removed making carbanion
carbanion pushes to double bond, expelling OH (anti elimination)
then H
2
O is deprotonated and attacks the double bond (anti addition)
180
o
shift
Step 3: Oxidation and Decarboxylation
(2R, 3S) isocitrate is oxidized by NAD
+

CO
2
kicks off, double bond movement to give ketone
Step 4: Oxidative decarboxylation
similar to transformation of pyruvate to Acetyl CoA
initial nucleophilic addition reaction by TPP ylid; decarboxylation; reaction with
lipoamide; elimination of TPP; finally transesterification with CoA
Step 5: Hydrolysis
phosphate adds via nucleophilic substitution reaction, giving tetrahedral intermediate
CoA is expelled as a leaving group
Histidine does nucleophilic substitution on phosphorous, expelling succinate and leaving
an O
-
on the substrate
(GDP does further nucleophilic substitution on phosphorous, yielding GTP and His)
Step 6: Dehydrogenation
like in beta oxidation, a hydrogen is abstracted, yielding a carbanion
the electrons get pushed to a trans double bond, expelling another hydrogen
Step 7: Hydration
H
2
O is deprotonated and attacks as a nucleophile, generating a carbanion
carbanion picks up proton in a net anti addition
Step 8: Oxidation:
oxidation by NAD
+
to give oxoacetate

Gluconeogenesis: making glucose from pyruvate
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not the reverse of glycolysis as one would think, but is related