Q.What is the function of Metabolism?

(a) To obtain and trap chemical energy from

substrates
(b) To build precursors to macromolecules from
substrates
(c) To assemble precursors into macromolecules.
Ex: DNA, Glycogen, Fat
(d) To degrade macromolecules into simpler
molecules
Catabolism and Anabolism
Catabolism is the oxidative breakdown of large
macromolecules into smaller, simpler
compounds. Usually it is accompanied by release
of free energy and trapping this energy as ATP
Anabolism is the enzymatic synthesis of large
macromolecules from smaller, simpler
precursors. Usually it requires input of energy.
AMPHIBOLIC-has both catab and anab components
e.g TCA cycle.
Differences between Catab & Anab
Enzymes-allows for regulation and direction.
Many enzymes may be same in a reversible
metabolic pathway but some will differ
Energetics- ATP made in Catab; used for Anab
Cofactors-NAD NADH used for catabolism
NAD(P)HNADP occurs for anabolism
Cellular localization may differ e.g cyto vs
mito
REGULATION of Metabolism

1. Availability & concentration of substrates and
COFACTORS. Need to regenerate cofactors
2.Availability/Need for ATP
3. Enzyme characteristics-heme,metal, dimers
4.Regulatory enzymes-often allosteric. ATP
catabolic reactions while ADP them.
Product inhibiton of anabolic reactions
5. Genetic control of amount of enzyme in cell.
Constitutive VS adaptive enzymes.
6. Hormonal regulation- chemical messenger
which or a metabolic reaction in another cell.

ENZYME RELATIVE Keq MASS/ACTION
ACTIVITY RATIO
____________________________________________________________________

Hexokinase 1 4000 0.08

Phosphoglucoisomerase 117 0.36 0.24

Phosphofructokinase 17 1000 0.03

Aldolase 52 0.0001 0.00001

Triosephosphate isomerase 1768 0.40 0.24

Glyceraldehyde 3P DH 295 1000 900

Phosphoglyceromutase 67 0.10 0.12

Enolase 105 4.0 1.4

Pyruvate Kinase 258 1000 40

CARBOHYDRATES/ GLUCOSE
Source of energy: Storage form of energy
Produces- fatty acids, cholesterol, steroids, some
amino acids e.g serine, glycine, alanine
Produces pentoses for RNA and DNA and cofactors e.g
NAD, NADP, FAD, Vitamin B12.

Glucose- C6H12O6, a hexose as is fructose. Glucose is an
aldose, fructose is a ketose. Ribose is a pentose ,
glyceraldehyde is a triose. These are monosaccharides.
Sucrose is a disaccharide of G and F. lactose is a
disaccharide of G and galactose. Polysaccharides made
up of many G
Glucose transporters and carriers
Passive carrier mediated glucose transport: No energy, G
moves down its conc. gradient. Blood glucose levels 4-8 mM.
GLUT 1 and 3 : Km= 1mM (high affinity), basal G uptake for
almost all tissues-RBC, brain, liver, heart etc
GLUT 2: Km= 15-20 mM (low affinity), senses high glucose
levels. Present in liver & pancreas
GLUT 4: present in adipose and muscle. Km = 5 mM. Amount
is increased when INSULIN triggers translocation from Golgi
to plasma membrane-one major action for insulin
Active Transport move molecules against their conc gradient-
require ATP or energy source/ gradient
GLUT 5: active transport linked to Na+ transport by the Gut
and kidney
SUMMARY SLIDE!
Tissue Affinit
y
Insulin Reg Pass/Active
GLUT1 So many! HIGH Nope. Passive
GLUT2 Liver, Pancreas low NO! Passive
GLUT3 So many! HIGH Nope. Passive
GLUT4 Muscle, Fat tbd YES!! Passive
GLUT5 GI tract
Kidney
Varies Yes Passive
SGLT1 GI tract
Kidney
HIGH Yes ACTIVE
SGLT2 GI tract
Kidney
low Yes ACTIVE
INSULIN
Released by cells of the pancreas in response to
high glucose. Function is to promote the use of
glucose by:
Increasing GLUT 4: glycolysis
( gluconeogenesis), glycogen synthesis (
glyc bkdown), fatty acid synthesis and protein
synthesis (their bkdown).
It works by activating or inhibiting rate-limiting
enzymes in these pathways or increasing or
decreasing synthesis of these enzymes-
posttranscriptional and transcriptional actions.
GLUCAGON/ EPINEPHRINE
Glucagon is made by the cells of the pancreas.
Epi is made by the adrenals (later lecture).
Glucagon is released in response to low blood
glucose, Epi is response to stress. Their functions
are to increase production of glucose especially
for use by brain, RBC, muscle/heart.
They do this by gluconeogenesis and glycogen/
fat/ protein breakdown. Basically the opposite of
insulin shown previously.
GLUCAGON works in liver & adipose, Epi-all tissues
DIABETES
Type 1-failure to produce insulin because of the
destruction of the cells.
Type II- failure to respond to the actions of
insulin-insulin resistance.
Associated with high blood glucose, impaired
glucose utilization and high glucose production,
bioenergetic problems/failure to thrive, ketosis
b/c increased fatty acid metabolism , protein
bkdown, glycosylation reactions and osmotic
pressure
GLYCOLYSIS
C6H12O6 + 2 NAD+ 2 ADP + 2 Pi
2CH3COCOOH (pyruvate or pyruvic acid)+ 2
ATP + 2 NADH. Irreversible, occurs in cytosol
of all cells. Pyruvate will be further
metabolized
Only source of energy for RBC, major source
for embryonic tissue, retina, adrenals, some
immune cells , exercising muscle.
NOTE: need to regenerate NAD from NADH.

The 10 reactions of glycolysis
Overall glycolysis reaction
Glucose + 2NAD
+
+ 2ADP + 2Pi

2Pyruvate + 2NADH + 2H
+
+ 2ATP + 2H
2
O

= irreversible steps in glycolysis
*
9
8
7
6
5
4
2
1
*
3
*
*
10
Hexokinase VS Glucokinase
Normal blood G conc 4-8 mM. 10-15mM after
meals
Glucose + ATP G6P + ADP Irreversible
HK - low Km for G ( 0.1-1 mM), in all cells, by
products G6P, ADP, reacts with other hexoses,
not affected by insulin, glucagon, Epi
GK- high Km for G ( 10 mM), in liver & pancreas,
not affected by products, specific for G, mRNA
levels by insulin,by glucagon & Epi
PHOPHOFRUCTO-1-KINASE (PF-1K)
F6P + ATP F1,6 Bis P + ADP Irreversible
(+) allosteric effectors-AMP, Pi, NH4, F1,6 bis P
(-) allosteric effectors- ATP, citrate
MAJOR (+) effector is F2,6 Bis P
F6P + ATP F2,6 Bis P + ADP F2,6 Bis P kinase RX
F2,6 Bis P F6P + Pi F2,6 Bis P phophatase RX
Insulin kinase butPhase. This will F2,6 and
then PF-1K. Glucagon/ Epi kinase butPhase,
this willF2,6 and then PF-1K. Covalent modif
Step 3:

-F6P converted to fructose 1,6-bisphosphate
(F16bP)
-Enzyme: Phosphofructokinase
-RATE LIMITING STEP
-Requires ATP so irreversible
-2 substrate binding sites
-Inhibitors: ATP, citrate
-Allosteric
-Activators: AMP, P
i
, NH4
+
, F16bP, (F26bP)
-Allosteric
-Also hormonal regulation
-F6P goes into side rxn to make F26bP
which is a major regulator of PFK
-Insulin leads to dephosphorylation of
F26kinase and F26phosphatase which
means more F26bP is produced and PFK is
upregulated
-Insulin indicates fed state, it tells
the body there is lots of glucose so it
stimulates glycolysis to use this up
-Glucagon/epi, via cAMP-PKA,
promote phosphorylated inactive
state of kinase and phosphorylated
active state of phosphatase


1,3-bisphosphoglycerate
ALDOLASE
F1,6 Bis P G3P + DHAP
DHAP can alpha glycero P, very important for
triglyceride and phospholipid synthesis or G3P
( triose P isomerase RX) and continue glycolysis.
Hence, F1,6 Bis P 2 G3P and we need to X by 2
all the next steps of glycolysis.
NOTE: when F1,6 Bis P 2 G3P, C1 of the
original G is equivalent to C6, C2and C5 cannot be
distinguished and C3 and C4 cannot be
discriminated from each other. Try to prove this.
G3P DH REACTION
G3P + NAD +Pi 1,3 Bis P glyceric acid + NADH
1,3 Bis PGA is a high energy compound. The next
step ( PGK ) ATP: G3P + ADP 3PGA + ATP. This
is substrate level phosphorylation no need for
mito, ets, oxygen. Arsenic uncouples
G3PDH by heavy metals-Hg, Cd,PB. We oxidized
an aldehyde (G3P) to an acid (3PGA) in these 2
coupled steps. The energy was trapped as a high
energy intermediate 1,3 Bis PGA, not released as
heat if G3P 3PGA directly.
1,3 Bis PGA can be mutated to 2,3 Bis PGA (HB-O2)

Pyruvate Kinase
PEP + ADP Pyr + ATP. Irreversible. PEP is a high
energy compound. Substrate level phosphoryl.
Requires monovalent cations like K or Na.
PK ATP, NADH, Acetyl CoA and Glucagon- or epi-
mediated Phosphorylation. by F1,6 Bis P and
insulin stimulated dephosph.
NOTE: ATP was made here & the G3P/ 3PGA
coupled steps. We made 4 ATPs ( 2 per triose)
and used 2 ATPs for the HK and PFK steps, net is 2
ATP/Glucose.
FATES OF PYRUVATE
RBC, exercising muscle, embryonic tissue
lactate via lactate dehydrogenase (LDH)
Yeast , conversion to ethanol via PDC & ADH
Aerobic cells, conversion to acetyl CoA via PDH:
Pyr + NAD+ CoA Acetyl CoA + CO2+ NADH
FATES of Acetyl CoA CO2 via TCA Cycle, ATP;
citrate which fatty acids
ketones bodies,cholesterol, steroids
Acetylation RX e.g histones
Lactate Dehydrogenase
Rxn: pyruvate+NADH+H
+
Lactate + NAD
+
Enzyme: lactate dehydrogenase (LDH)
Reversible
Anaerobic
RBC have no mitochondria so this is their only
way to get NADH reoxidized back to NAD
+
(req.
for glycolysis, their only source of ATP)
Net rxn: glucose +2ADP+Pi 2 lactate +2ATP
LDH Tetramer: 2H & 2M chains
o 5 isoforms:H4, H3M, H2M2, HM3 and M4
H4 and H3M: Brain or Heart
M4 and M3H: RBC & skeletal muscle
H subunits have high affinity for lactate &NAD
+
; pyruvate --| H4


dehydrogenase
Enzyme Name Cofactor Rxn
E1 Pyruvate Decarboxylase Thiamine
pyrophosphate
(TPP)
Oxidative decarboxylation
of pyruvate
E2 Dihydrolipoyl transacetylase Lipoamide Transfer of acetyl group to
CoA
E3 Dihydrolipoyl dehydrogenase Riboflavin (FAD) Regenerates Oxidized
lipoamide
Regulated enzyme Inhibited by Hormonal regulation
E1 ATP
PDH Kinase inhibits E1
PDH Phosphatase activates E1 and its action is
increased by insulin
E2 acetyl CoA
E3 NADH
Pyruvate Dehydrogenase Enzymes
Product inhibition
High energy
signal inhibition
TCA CYCLE
In mito of all aerobic cells. IRREVERSIBLE
Acetyl CoA + 3 NAD + FAD+ GDP+ Pi+ 2 H2O
2 CO2 +3 NADH+FADH2+GTP+CoASH
ENERGETICS: 3 NADH 7.5 ATP; GTP=ATP
FADH2 1.5 ATP 10 ATP/Acetyl CoA
Of the 6 carbons in G, C3,4 CO2 in PDH RX
C1,2,5,6CO2 in TCA cycle
STEP 4
1.Kg + NAD
+
+ CoA-SH Succinyl-CoA+ NADH + H
+

+CO
2
1.Kg Dehydrogenase is a complex of enzymes
2.E1= Kg Decarboxylase has Thiamine PP as cofactor
1.inhibited by ATP
3.E2 = uses lipoic acid
1.inhibited by succinyl CoA
4.E3 = uses FAD & NAD to regenerate Lipoic acid
1.inhibited by NADH
Step 5
1.Succinyl CoA + GDP +P
i
Succinate +CoA-SH +
GTP
1.Enzyme = Succinyl CoA synthase (Thiokinase)
2.CEDERBAUM WORKED ON THIS enzyme
(and he is adorable)
Steps 6, 7 , and 8
1.Succinate + FAD Fumarate + FADH
2
1.Enzyme: Succinate dehydrogenase
2.Fumarate + H
2
0 Malate
1.Enzyme: Fumarase
3.Malate +NAD
+
OAA + NADH + H
+
1.Enzyme: Malate dehydrogenase
*each rxn is reversible but
Malate dehydrogenase favors
OAAMALATE
ANAPLEROTIC (NOT EROTIC) RX
Intermediates of the TCA cycle can be pulled out
into other RX and pathways. OAA will not be
regenerated , TCA stops.
Anaplerotic RX are replenishing RX, fill in the
pulled out intermediates.
#1 in next slide is pyr carboxylase (PC), only in mito
Not shown is the PEP carboxykinase RX: PEP +
CO2+ GDP OAA + GTP (PEPCK in mito and/or
cyto)
PC & PEPCK very important for gluconeogenesis

Regulation of the TCA cycle
Rate of electron transfer chain to reoxidize
FADH2 & NADH. RESPIRATORY CONTROL
ATP& NADH citrate synthase, ICDH, KGDH
Concentration of and regeneration of OAA e.g
OAA glucose, when G made, need toOAA
Acetyl CoA is also produced from oxidation of
fatty acids, several amino acids, ethanol so
usually not limiting.
Final Products
2 CO
2
s
1 FADH
2
(= 1.5 ATP)
3 NADH + 3H
+
(= 7.5 ATP)
1 GTP (= 1ATP)
Total = 10 ATP/ Acetyl CoA
OVERALL YIELD!
Mitochondrial Carriers
Carrier Description
Phosphate
exchanges Pi with OH
Dicarboxylate exchanges Pi/malate/succinate for
eachother
Tricarboxylate

exchanges citrate, isocitrate, malate
or PEP for eachother
Alpha Ketoglutarate exchanges alphaKG for malate
Pyruvate exchanges pyruvate for OH or ketone
bodies
Glutamate exchanges glutamate for OH
Aspartate exchanges asparate for glutamate
Adenine nucleotide exchanges ADP for ATP
SHUTTLES
NADH and NADPH cannot enter or leave mito
Need substrate shuttles to transport them. Most
imp. for NADH are the -glycerophosphate (GP)
and malate-aspartate (MA) shuttles. These are
also used for metabolism of other RX producing
NAD(P)H e.g ethanol.
Transamination is the transfer of an alpha amino of
one amino acid to a keto acceptor to new aa
and a new keto acceptor
How to distinguish between the GP & MA shuttles
Malate-Aspartate Shuttle
Malate dehydrogenase
Malate dehydrogenase
Aspartate
aminotransferase
(GOT)
Carriers 2, 3, 4
Carrier 7
Carrier 4
Aspartate
aminotransferase
(GOT)
Cytosol Mitochondrial matrix
Kg
+
CO
2
carrier 4
cyto
ICDH
mito
ICDH
carrier 3
isocitrate isocitrate
NADP
+
NADPH
NADP
+
NADPH
NAD
+
NADH
trans
hydro-
genase
Kg
+
CO
2
GLYCOGEN METABOLISM
Glycogen a storage form of G, made up of many G
units linked by 1C of one G to the C4 of another
G. Also C1 to C6 links make branches.
Glycogen made under high- energy, carbs & G
Glycogen broken down low- energy, carbs & G :
vigorous exercise/ stress: diabetes
Stored mainly in liver and muscle. Function of liver
Glyc is to produce G for use by other tissues
needing energy. Function of muscle Glyc is to
produce G for use of muscle itself
Glycogen Breakdown
Catalyzed by phosphorylase and debranching
enzyme many G1P + 1 G where a branchpoint
G1PG6P via phosphoglucomutase
G6PG via G6Pase in liver OR glycolysis in
muscle. Note that G6Pase is by glucagon/Epi
Phosphorylase is activated when P by
phosphorylase kinase (PK) which itself is
activated by cAMP-dependent PKA. Thus
glucagon in liver and Epi in liver and muscle
Glyc breakdown. Insulin promotes the deP
state of PK and phosphorylase which activities
Glycogen Synthesis
GG6PG1PUDPG. Need exisiting primer-
Glycogen (n) + UDPG Glycogen ( n+1) + UDP
Catalyzed by Glyc Synthase ( GS) and Branching enzyme
GS active in de P state (GS-OH) and inactive when P
(GS-OP). Insulin, via protein phosphatase 1 (PP1)
promotes the de P state while cAMP PKA promotes
the P state. Same with PK and phosphorylase. Note
deP state GS and Glyc synthesis but PK and
Glyc breakdown-insulin while P state PK and
Phosphoryalse & Glyc breakdown, but GS
Glucaon/Epi
MORE GLYCOGEN REGULATION
I am kind of tired. Need coffee,a PDE inhibitor
AMP Phos-OH ( low activity) which will activity a bit
and some Glyc breakdown.
ATP & G6PPhos-OH
G6P GS-OP ( low activity) which will some Glyc
synthesis
Glucaon/Epi PP1 by P and also by activity of a PP1
inhibitor by P. InsulinPP1 by deP and by also by
inactivating the PP1 inhibitor.
Liver Phos is a glucose sensor-binds PP1 when G is not
present so PP1 not effective but releases PP1 when G
is present so now PP1 starts to do its job
F2,6 Bis P in liver VS Muscle
Why didnt the G6P made from glycogen
glycolysis in the liver but did in the muscle?
Recall, F2,6 bis P was the major (+) effector of PF-
1K. Its production was by insulin which the
F2,6 kinase but the F2,6 bis Phase by covalent
modifications. Glucagon/ Epi in liver the kinase
&the Phase so F2,6 levels & glycolysis. In
muscle, different isoforms of the kinase and
Phase exist than in liver such that Epi the
kinase &Phase,therebyF2,6 BisP &PF-1K
Liver Muscle
Glucose tissues Glucose glycolysis
Glucagon + Epi stimulate glycogen
phosphorylase
Epi stimulates glycogen phosphorylase
Epi stimulates G6Pase
Glucagon + Epi decrease F26bP so
glycolysis decreased
Epi increases F26bP so glycolysis
increased
Phosphorylation decreases F26bP kinase
and increases phosphatase activity
Phosphorylation increases F26bP kinase
and decreases phosphatase activity

Phosphorylase: glucose sensor. No
glucose: phosphorylase binds protein
phophatase 1 =>prevents deP=>
active Phosphorylase, inactive
synthase (no glycogen synthesis!) and
vice versa!

Epinephrine=> increases Ca2+, binds
calmodulin =>activates phosphorylase
kinase => glycogen breakdown signal

The liver and muscle isoforms of F2,6-bP kinase and phosphatase are opposites. For
more detailed info on this see the last text page of Cederbaums lecture.
PENTOSE P PATHWAY
Function s to produce NADPH, ribose 5 P,
interconversions of C3,C4, C5, C6 and C7 sugars.
Active in cytosol of liver, RBC, adipose, adrenals, mammary tissue
Regulated by Conc. of G6P, NADP/NADPH. Insulin small G6PDH
First 2 steps catalyzed by G6PDH & 6PGADH- IRREV
3 G6P3CO2+6 NADPH +3Ribulose 5P. Step 3 is
3 Ribulose 5P3 Ribose 5P PPIsomerase-REVERSIBLE.
Rearrangements: Transketolase,Transaldolase,Transketolase RX
3 Ribose 5P2F6P+ G3P(=0.5 G6P); 2.5 G6P made. TPP cofactor for TK
NOTE G6P & G3P can R5P by reversing Rearrangement RX
CO2 came off C1 of G6P, can come off other Cs after rearrangement
REARRANGEMENT RXs
a) 3 G6P + 6 NADP
+
3 CO
2
+ 6 NADPH + 3 Ribulose 5P (G6PDH and 6-PGADH steps)
b) 1 Ribulose 5P 1 Ribose 5P (phosphopentoisomerase rxn)
c) 2 Ribulose 5 P 2 Xylulose 5P(phosphopentoepimerase rxn)
d) Ribose 5P + Xylulose 5P Glyceraldehyde 3P + Sedoheptulose 7P ( 1
st
transketolase rxn)
(C5) + (C5) (C3) + (C7)
e) Glyceraldehyde 3P + Sedoheptulose 7P Erythrose 4P + Fructose 6-P (transaldolase rxn)
(C3) + (C7) (C4) + (C6)
f) Erythrose 4 P + the second Xylulose 5P from rxn (c) Glyceraldehyde 3P + Fructose 6P
(C4) + (C5) (C3) + (C6)
( second transketolase rxn

NET RX: a) 3 G6P + 6 NADP+ 3 CO
2
+ 6 NADPH + 3 Ribulose 5P (G6PDH and 6-PGADH steps))
(b f) 3 Ribulose 5P 2.5 G6P rearrangements
Net 6NADP
+
+ 0.5 G6P 3 CO
2
+ 6 NADPH


OXIDATIVE STRESS & PPP
Hydrogen peroxide, H2O2,made in aerobic cells
from mito ets or autooxidation of ferrous
hemes like hemoglobin. H2O2 removed by
catalase and by glutathione peroxidase, GPX,
which uses glutathione,GSH, a tripeptide.
H2O2 + 2 GSH 2 H2O + GSSG GPX RX
Note GSH is oxidized to GSSG and must be
reduced back to GSH by glutathione reductase
GSSG + 2NADPH2 GSH +2 NADP
G6PDH DEFICIENCY
Most common inborn error of metabolism
Complete deficiency is embryonic lethal.
Certain drugs G6PDH, can RBC hemolysis,
anemia. Those with low G6PDH sensitive to
oxidant stress produced by drugs, chemicals,
foods (Fava beans), high O2, high altitudes
Wernicke Korsakoff Syndrome- poor memory,
orientation,gait, mental function/ neuropsyc.
Disorders. Due to 10X in Km for TPP by TK
GLUCONEOGENESIS
Occurs with low G/CH diet,fasting/starvation,when
G is needed for quick & rapid energy for muscle.
Liver & kidney. Compartmentalized cyto & mito.
Most common substrates-lactate & aapyr.
2 Pyr+ 2 GTP +4 ATP+ 2 NADHG + 2 GDP+ 4 ADP +
2 NAD + 6 Pi. Where is energy from?
Most, but not all, steps are reversal of glycolysis.
To bypass PK, PF-1K, & GK/HK, need gluconeo
enzymes PC, PEPCK, F1,6 Bis Phase, G6Pase These
are by glucagon/Epi and by insulin.
Step 2&3: Pyruvate OAA PEP
Pyruvate converted to PEP via
two steps to bypass the
irreversible pyruvate kinase
reaction
Step 2: Pyruvate carboxylase
reaction
Pyruvate + ATP + CO2 OAA
+ ADP +Pi
Happens in mito
Step 3: PEP carboxykinase
(PEPCK) reaction
OAA + GTP PEP + CO2 +
GDP
Happens in mito and cytosol
Step 6&7: F6P G6P glucose
- F1,6 bis
phosphatase:
stimulated by low
energy signals
(AMP, Pi, NH4+,
glucagon, epi) and
inhibited by high
energy signals (ATP,
citrate, insulin)
- G6Pase: stimulated
by glucagon and
epi, inhibited by
insulin
CORI CYCLE
or exercising muscle
REGULATION
FATTY ACIDS
Functions:
Major source of energy for most tissues but not
RBC or brain
Major storage from of energy as triglycerides
Make up phospholipids & glycolipids of biological
membranes
Produce signal transduction molecules e.g inositol
Phosphates, Diacylglycerol
Produce prostaglandins, leukotrienes

FA OXIDATION
Palmitoyl CoA: C16+7 FAD+7 NAD+7CoA+7H2O
8 Acetyl CoA +7 FADH2 + 7 NADH:
Energetics: 8 Acetyl CoA 80 ATP
7 FADH2 10.5 ATP 7 NADH17.5 ATP
Total 108 ATP made 2 ATP to activate =106ATP

Occurs in Mito & some in peroxisomes
-oxidation pathway
Step 1: Fatty acid
fatty acyl CoA
via Acyl CoA
synthase in
mitochondria
Short and medium
chains enter mito
directly; long
chains utilize
carnitine
transporter
-oxidation pathway
4 enzyme catalyzed
reactions to remove 2
carbon fragment at a
time produce acetyl
CoA plus a new fatty
acyl CoA shortened by
2 carbon atoms
Acetyl CoA can then
enter Kreb cycle
Repeats until all the
carbons are oxidized to
acetyl CoA
Each round produces:
one FADH2 and one
NADH
Ex. C18 fatty acid will
undergo 8 rounds
ODD CHAIN FA
Basically same as even chain FA- -oxidation of
C17 FA CoA 7 Acetyl CoA +Propionyl CoA
CH3CH2COCoA+ CO2D-MethylmalonylCoA via
propionyl CoA Carboxylase ( Biotin) L-MMCoA
via MMA racemase Succinyl CoA via MMA
Mutase. Mutase requires deoxyadenosyl B12
to catalyze this remarkable rearrangement RX
Will return to this in our B12 lecture
Regulation of -oxidation
Availability of fatty acids via activated
hormone sensitive lipase
Availability of carnitine.
Malonyl CoA, the product of the rate-limiting
enzyme of fatty acid synthesis (next lecture)
inhibits carnitine acyl transferases 1 and 2.
Rate of the electron transport chain
Q: Explain possible major problems for patients A, B, C in oxidizing palmitate
into CO2:
Substrate Rate of CO2 Production
Control A B C
Palmitate 100% 10% 10% 10%
Palmitoyl-coA 100% 100% 10% 10%
Palmitoyl-
Carnitine
100% 100% 100% 10%
Acetyl-coA 100% 100% 100% 100%
FA SYNTHESIS
8 Acetyl CoA+ 7ATP+ 14NADPH
C16 palmitoyl CoA+7CoA +7ADP+7Pi + 14NADP
Compartmentalized between Mito & Cyto
Acetyl CoA from Pyr ( G) & AA ( not from FA)
NADPH from PPP, Transhydro & isocit shuttle &
malic enzyme
Substrates and Metabolic Conditions
Activating conditions
High glucose
High protein
Insulin
Activates SREBP
Inhibiting conditions
Glucagon
Inhibits SREBP
Malonyl CoA
Inhibits acyl carnitine transferase that brings FA into mito for B-oxidation
Location
Cytoplasm of most cells especially liver
Substrate
Acetyl CoA (transported to cytoplasm as citrate from glycolysis)
Energy demands
ATP and NADPH

Rate Limiting Step
Acetyl CoA + ATP + CO
2
malonyl CoA + ADP + P
i
Enzyme: Acetyl CoA carboxylase
Cofactor: biotin
Activators:
Citrate
Insulin (dephos ACC and stimulating it)
Inhibitors:
palmitoyl CoA (product)
AMP activated kinase (phosphorylates ACC)
Glucagon/cAMP-PKA (phosphorylates ACC at another site)
REGULATION
Many of the lipogenic enzymes ACC, FAS, ATP-
citrate lyase, malic enzyme are induced by insulin
which activates processing of the master
transcriptional activator Sterol Regulatory
Element Binding Protein (SREBP)to its active
form.
High glucose activates Carbohydrate Response
Element Binding Protein which upregulates many
genes involved in carbo and FA synthesis ( JC
paper).
FATTY ACID OXIDATION
Three patients(ABC)have trouble ox Palm to CO2
CONTROL A B C
SUBSTRATE RATE OF CO2 PRODUCTION
Palmitate 100 10 10 10
Palm CoA 100 100 10 10
Palm Carnitine 100 100 100 10
Acetyl CoA 100 100 100 100
Fed State
Basal State
Starved State