Chapter 18 Glycogen Metabolism
I. Purpose: Glycogen is a branched polymer of glucose; it is the stored form of G. The many
branches each have a C#4 end at which GP and GS can act for rapid response.
Glycogen is stored after a meal for release: From liver when blood [G] is low to supply brain; OR
In muscle for rapid activity.
A. Main Enzymes
1. Glycogen Phosphorylase (GP): releases G as G1P:
Gn + Pi  G(n-1) + G1P (no ATP cost)
GP removes G only from C#4 ends of chains that are at least five G’s from a branch
(G1P equilibrates with G6P; this is not regulated) G1P<----> G6P
2. Glycogen Synthase (GS): adds G (as UDP–G) only to C#4 ends of chains.
a) Preliminary: G  G6P  G1P ; then: G1P + UTP  PPi + UDP–G
b) GS rxn: Gn + UDP – G  UDP + G(n +1)
B. Other Enzymes of Glycogen synthesis/breakdown:
1. Debranching enzyme: after GP has removed all but the last 4 G residues from a branch,
this enzyme: 1) catalyses transfer of 3 G residues to the C#4 end of a nearby branch and
2) catalyses hydrolysis of the 1  6 linkage, producing G
2. Branching Enzyme: transfers C#1 of a 7G residue segment (from a branch at least 11 G
long) to the C#6 of a residue at least 4 G away.
II. Regulation of GP, GS
1. GP is designated by 2 systems a/b and m/o, which we will not use. Instead, we will refer to
the enzyme as: phosporylated (P) or dephosphorylated (DP) (GS is also P, DP).
2. GP and GS are phosphorylated in response to glucagon (in the liver) (low blood [G]) and
adrenalin (muscle) (fight/flight), activating GP for release of G and inactivating GS.
3. GP kinase (GPK): GP + ATP  ADP + GP–P.
4. They are dephosphorylated in response to insulin inactivating GP, activating GS to store
G.
5. Regulatory effects
a. GP-DP is:
1) activated by AMP. MR: GP provides GlP  G6P for ATP production in glycolysis,
and in OP via PDH, TCA, ET, OP. ML: [AMP] is high when ATP use is rapid and ATP production is
needed.
2) inhibited by ATP. MR in 1). ML: when [ATP] is high, GP doesn’t need to release G to
produce more
3) inhibited by G6P. MR: G6P is an indirect product of GP. ML: when [G6P] is high, GP
doesn’t need to make more.
b. GP-P is inhibited by glucose. MR: G is indirect product: GlP  G6P  G. ML: no need
for more fuel when plenty is available
c. GPK is activated by Ca2+. MR: GPK activates GP, which provides fuel for ATP
production. ML: Ca2+ triggers muscle contraction, ATP production is needed.
d. GS-DP is activated by G6P: MR: G6P is indirect substrate: G6P  GlP  UPD-G
(feed forward) ML: when G6P is plentiful, it’s time to store G.
III. Hormonal Regulation of Glycogen Metabolism.
A. Enzyme Phosphorylation
1. The “hunger hormone”, glucagon is a signal to release G to blood from the liver via
glycogenolysis and gluconeogenesis. Liver GP is activated, GS inhibited.
2. Adrenalin (epinephrine) is a signal to “break down” muscle glycogen to produce G6P for
ATP production for fight-or-flight. Muscle GP is activated, GS inhibited.
3. Mechanism: When either of these binds its cell-membrane receptor,
a. the hormone-receptor complex binds to adenylate cyclase and activates it to catalyse
ATP  PPi + cAMP
b. cAMP is the internal or “2nd” messenger. It binds to protein kinase (PrK) regulatory (r)
subunits, dissociating them from the catalytic (c) subunits, which are then active.
c. PrK catalyses the phosphorylation of a variety of proteins, including:
Glycogen synthase, inactivating it
Glycogen phophorylase kinase (GPK), activating it.
the tandem E (G’lysis)
pyruvate kinase (G’lysis)
AcoAcarboxylase (FA synthesis)
d. GPK-P catalyses phosphorylation of glycogen phosphorylase (GP), activating it.
e. Net hormonal effect: GP activated: Gn  G; and GS inactive, preventing opposition to
GP.
B. Enzyme Dephosphorylation
1.Dephosphorylation of these enzymes (GPK, GP, GS) is catalyzed by phosphoprotein
phosphatase 1 (PP1).
2. a. Phosphorylation of a regulatory glycogen binding protein, GM in response to insulin
(which causes dephosphorylation of other Es) at site 1 activates it resulting in the opposite
activities to the above (GS active to store the plentiful G, GP not, to prevent opposing GS).
b. Phosphorylation of GM at site 2 (alone or in addition to site 1) by PrK inactivates it,
preventing it from opposing PrK.
3. PrK also phosphorylates phosphoprotein phosphatase inhibitor 1 (PPI-1) causing it to bind
to and inactivate PP1.
4. In Liver, the switch from the phospho- to the dephospho- state of the above cannot occur
without the accumulation of glucose: “GP is the glucose sensor”:
a. In the phospho (active) form, the P’s on GP are “buried” where PP1 can’t get at them.
b. When G binds to active GP-P, its conformation changes, “exposing” the P’s so PP1 can
“clip them” off.
c. While PP1 is bound to GP-P in the R form the phosphatase (PP1) is not active toward
other phosphoproteins. Only after GP-P binds G and PP1 dephosphorylates GP is PP1 released
and active.
d. PP1 has a much higher affinity for GP than for GS, GPK, etc, so it must first “work its
way through” ~ all the GP-P, dephosphorylating it, before it has much effect on GS.
C. Amplification cascade
GP and GS are allosterically regulated by intracellular metabolites like AMP, ATP, G, and G6P. So
why has a complex hormonal regulation scheme evolved? The big advantage is speed and
magnitude of response: each enzymatic step amplifies the signal, and subsequent ones multiply
previous ones:
1. each hormone-receptor complex activates one adenylate cyclase, which can produce, say
1000 cAMP/sec.
2. 4 cAMP can --> 2 active PrK which can produce, say, 100 GPK-P/sec.
3. Each GPK-P can phosphorylate, say, 100 GP/s.
4. So, the one H-R complex results in: 1000 cAMP x 2PrK/4 cAMP x 100 GPK-P/PrK x
100GP-P/GPK-P = 5,000,000 activated GP/sec, rather than 1 Enzyme/1 effector. That's why it’s
called the" amplification cascade".
IV. Glucokinase (GK)
1. GK catalyzes G + ATP  G6P + ADP, same as HXK.
2. GK is a liver enzyme; muscle doesn’t have it (has HXK).
3. The properties of GK are more suited to maximum glycogen synthesis when [G] is high.
HXK can also support rapid glycogen synthesis, but not as well as GK.
4. HXK is “designed” to keep up with extremely rapid glycolysis (if that’s the pace PFK sets):
when PFK consumes F6P rapidly, G6P is also consumed rapidly, (G6P F6P) so that HXK is
not inhibited by G6P.
5. But GK is not inhibited by G6P, so when [G] is high it can produce a much higher [G6P]
which kinetically pushes glycogen synthase: via G6P  GlP  UDPG
6. GK has a much higher Km (lower affinity) for G so its rate is nearly proportional to [G]
across the physiological [G] range.
Chapter 25 FAs (fatty acids)
I. Introduction
1. FAs are a much more efficient form of stored fuel: 9kcal/g (9 Cal/g) vs. (4 Cal/gG); also
glycogen binds two times its weight of H2O. A typical man would have to store ~ 90 kg of glycogen
(~200lbs) if he was to have the same energy as in the ~15 kg fat he stores.
2. Although glycolysis is a major fuel consuming pathway, FAs are the main fuel (except in
brain, RBCs, rapid muscle activity).
3. Because of the above, glycogen storage is limited and “xs G” is converted to fat via
glycolysis, PDH, CS and FA synthesis.
II. FA use as fuel:
A. 1. FAs are released (from storage as triacylglycerol) by the hydrolytic action of hormonesensitive lipase, which is activated by phosphorylation by PrK in response to adrenalin or
glucagon, deactivated by dephosphorylation by PP1 in response to insulin.
2. FA’s then travel from adipose cells (“cytosol” is mainly a fat globule) in blood to cells that
use them.
3. FA’s are prepared in the cytosol (cytoplasm) for transport to the mitochondrial matrix in
FA activation:
a. FA + ATP  PPi + FA–AMP;
b. FA–AMP + CoASH  AMP + FA – SCoA (costs 2 ATP)
4. CoA from cytosol doesn’t enter matrix (or vice-versa).
a. Instead, on outer surface of inner membrane, FA is transferred to carnitine (releasing
CoASH to cytosol) in a rxn. catalyzed by carnitine acyltransferase I (CATI) (aka Carnitine
PalmitoylTransferaseI, or CPTI).
b. A transport protein in the inner membrane brings fatty-acyl carnitine into the matrix (in
exchange for carnitine delivered outside).
c. CATII (CPTII) on inner surface transfers FAcyl group from carnitine to CoASH.
(Palmitate is the 16C saturated FA)
B. 1. -oxidation converts the fatty acyl group to ACoA. Net reaction for palmitate:
C15H31COSCoA + 7FAD + 7CoASH + 7NAD+  8ACoA + 7FADH2 + 7NADH
CH3(CH2)14CO2SH + 7CoASH +7NAD+ + 7FAD
8ACoA + 7NADH + 7FADH2
2. ATP production from -oxidation of palmitate (+ TCA, ET, and OP):
a. 8XTCA: +8GTP + 24NADH + 8FADH2
b. ET: -31NADH – 15FADH2
c. OP: [+3(31) + 2(15)] ATP = + 123 ATP
d. 123ATP + 8GTP – 2 “ATP” (ATP  AMP in FA acivation ) = 129ATP
C. Ketone body production
1. The moderate rate of production of acetoacetate,  hydroxybutyrate and acetone that
occurs normally in liver mito. matrix delivers “water soluble FA fragments” to cells via blood for use
as fuel.
2. Since this process involves unregulated enzymes, the buildup of ACoA in diabetes
overproduces these compounds to toxic levels.
III. FA Synthesis (a liver pathway)
The net effect is to build up the CH2 chain by joining ACoAs’ acetyl groups and reducing (and
hydrogenating) the C=O.
A. The ACoAs for FA synthesis don’t come from  oxidation. Rather it’s the “xs G” that enters
liver cells after a meal and goes through insulin stimulated glycolysis and PDH.
But PDH is in matrix, FA sythase is in cytosol:
1. high ACoA from PDH stimulates PC  high oxac.
2. (ACoA + oxac  citrate) in matrix; then transport citrate to cyosol.
3. citrate cyto  (ACoA + oxac) cyto (catalyzed by citrate lyas e)
4. oxac + NADH  malate + NAD+ then, mal can enter matrix, OR
5. in cyto: mal + NADP+  NADPH + pyr + CO2 ; (pyr goes to matrix). this rxn is catalysed
by the malic enzyme
6. The NADPH is needed for FA synthesis (below)
7. The cyto ACoA is activated for joining by conversion to malonyl CoA (carboxylation):
ACoA + CO2 +ATP ---> ADP + Pi + mal CoA
B. FA synthase: in E Coli, this consists of a number of separate enzymes, but in animals 2
identical subunits each contain the enzyme activities for all the rxns ( oxidation has a different
enzyme for each step).
1. The substrate remains bound to the long phosphopantethein prosthetic group (Fig. 25-29,
p931), which “carries” it to each of the various active sites. This is on ACP (acyl-carrier protein)
2. Phases of reaction “cycle”:
a. Loading: the acetyl group of ACoA is transferred to a cys-S (viaACP) and the malonyl
group of mal-CoA to ACP-S.
b. Condensation, Reduction: C2 chains are linked, releasing CO2, then reduced to (CH2)2.
c. Reloading: existing chain transferred to cys-S; next malonyl group to ACP-S (each mal
of mal CoA goes onto ACP, only acetyl group of ACoA (and existing chain) go onto cys-S
3. Release: FA hydrolyzed from ACP
IV. Regulation of FA Metabolism
ACoAC
A. ACoA Carboxylase (ACoA  mal CoA)
1. Inhibited by palmitoyl CoA. MR: indirect product (mal CoA  palmitate pal CoA)
ML: If [pal CoA] is high, it is being produced faster than it can be used, production can slow)
2. Activated by citrate. MR: indirect substrate; citrate  oxac + AcoA, the substrate
ML: when[citrate] cyto is high, [citrate] mito is very high, fuel is plentiful, time to store it
3. Inhibited by phosphorylation in response to glucagon or adrenalin. These hormones
promote fuel mobilization to make fuel available, so they inhibit storage.
4. Activated by dephosphorylation in response to insulin. Insulin “signals fed state”, when [G]
is high it’s time to store C as glycogen and FAs.
5. Phosphorylation shifts ACoAC from active polymer form to inactive monomer form.
B. Carnitine Acyl Transferase I (CATI) (transport of FAs into matrix for  oxid’n).
Inhibited by mal CoA. MR: mal CoA is the product of the committed step in the opposing
pathway, FA synthesis. ML: When [mal CoA] is high, FA synthesis is rapid (in liver), with the
purpose of export of these FA’s for storage. Inhib of CATI prevents consumption from working
against synth.
Chapter 26 Amino Acid (AA) oxidation
A. Introduction
1. Part of the C’s of some of the AAs are convertible to ACoA, either directly or via
acetoacetate or pyr. (and less directly, so are the others via TCA int  oxac  PEP  pyr 
ACoA.) (These are the “ketgenic AAs.) So, these C’s of xs AA intake (in relation to need for
protein synth) are used as fuel, just like dietary CH2O’s, fats.
2. Part (or all) of the C’s of 18 of the AAs can be converted to TCA intermediates, which can
PEPCK
be converted to G (TCA int  oxac  PEP  G). These are referred to as the “glucogenic”
AAs.
AAs from digestion of muscle protein are the main source of C for gluconeogenesis in CH2O
starvation
B. Transaminations (trnsams) and Oxidative Deamination
1. Each AA can be converted to the corresponding  keto acid by at least one transaminase.
This AA is oxidized in this rxn, but  kg is reduced to glu at the same time so not a net AA
oxidation
2. Net oxidation occurs by coupling of trnsam with glutamate dehydrogenase (GDH).
3. GDH: glu + NAD+   kg + NADH + NH3 (this rxn running in reverse when [NH3] is
very high depletes TCA ints, interferes with TCA +ET + OP in brain cells and causes the
delirium/dementia in liver damaged patients)
4. The amino group transferred to kg (---> glu) is toxic when released as NH3 in GDH. This
ammonia is detoxified by conversion to urea in the urea cycle (NH3 can be excreted).
C. Regulation of AA Oxidation
1. GDH is inhibited by ATP and GTP and activated by ADP and GDP.
MR: GDH + trnsam  TCA ints   TCA  ET  OP: ATP production
ML: If [ATP] or [GTP] is high, more is not needed; if [ADP] or [GDP] is high, ATP
synthesis is needed; TCA  ATP
2. Carbamoyl Phosphate Synthetase I (CPSI) is activated by N-acetylglutamate (NAG).
MR: is produced from ACoA and glutamate: ACoA + glu  NAG. A high [ACoA] and/or a
high [glu] increases the rate of NAG production and the [NAG], so the [NAG] indicates the levels of
AcoA and glu.
MR, ML for ACoA: when [ACoA] is high there is a need for oxac to react with ACoA in the
CS reaction. GDH + trnsam can produce TCA ints from AAs at a high rate only if CPSI consumes
the ammonia product of GDH.
MR, ML for glu: when [glu] is high it has been produced by a high rate of trnsam and there
is a need to convert it to  kg in GDH to maintain [ kg] for TCA and trnsam. CPSI must consume
the ammonia product of GDH in order for GDH to go.
Diabetes Mellitus and Review of Hormonal Regulation of Metabolism
Enzymes
(Pathways)
Glucagon Adrenaline
(* = Phosphorylation)
Liver
Muscle
Insulin
(Dephospho)
Liver
Muscle
Glycogen synthase*
glycog phosphorylase*
(synthesis/olysis)
inh
act
olysis
inh
act
olysis
act
inh
synth
tandem*: PFK2
FBPase2
[F2,6BP]
PFK (Not*)
FBPase (Not*)
Pyruvate Kinase*
(glycolysis/gluconeo)
inh
act
low
inh
act
inh
neo
act (hrt)
inh (hrt)
high (hrt)
act (hrt)
act
inh
high
act
inh
act
lysis
‘lysis (hrt)
PDH (* but not in resp
to glucag/adren)
ACoA carboxylase*
[malonyl CoA]
lipase*
FA (synth/oxid’n)
act
inh
synth
act
inh
low
act (adipose)
oxid
oxid
act
high
inh (adipose)
synth
1. In type I diabetes, insulin is underproduced, glucagon is overproduced. So, even after
a meal when blood [G] is high, the liver is responding to glucagon by producing G (for
export to blood?) via gluconeogenesis and glycogenolysis and is also doing rapid FA and
AA oxidation. (It should be responding to insulin and doing glycogen synthesis, and
glycolysis/PDH/FA synthesis.)
2. G’neo consumes TCA intermediates (ox ac PEP). This depletes TCA because PC
lacks pyr for pyr  ox ac. Meanwhile, active FA oxidation produces high [ACoA],  rapid
ketone body synthesis. If this goes too far it results in ketoacidosis, even coma, death.
3. Other insulin effects: increases uptake of G into muscle and adipose tissue; also
increases uptake of some AA’s and protein synthesis. Lack of these effects results in: a)
AA’s being used for gluconeo rather than protein synth, muscle wasting, b) low glycolysis
in adipose  low glycerol phosphate (from DHAP)  low FA storage as triacylglycerol.
4. Very high blood [G] exceeds capacity for reabsorption in distal tubule in kidney, G
“spills” into urine.
5. Non-insulin-dependent diabetes in obesity is very common, results from overutilization
of insulin response to eating. This causes decreases in insulin receptors by
downregulating receptor synthesis. Cells can’t respond. May have normal insulin
production or decreased. (“Adult onset”)
6. Type I is an autoimmune disease. A protein on the surface of the insulin secreting cells
of the pancreas is very similar in structure and sequence to a surface protein of the
coxsackie virus, which causes flu like symptoms. After infection, some of the person’s
killer T cells have become activated against this protein, kill pancreatic cells.