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Glycolysis

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Zach Morrison

on 26 December 2013

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Transcript of Glycolysis

Glucose
Glucose-6-Phosphate
Fructose-6-Phosphate
Fructose-1,6-Bisphosphate
Glyceraldehyde-3-Phosphate
Dihydroxyacetone
Phosphate

1,3-Bisphosphoglycerate
3-Phosphoglycerate
2-Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
Lactate
Glucose-1-phosphate
Glycogen
Hexokinase, Glucokinase
Phosphoglucose
Isomerase
Phosphofructokinase-1
Aldolase A/B
Phosphotriose
Isomerase
Glyceraldehyde-3-Phosphate
Dehydrogenase
Phosphoglycerate
Kinase
Phosphoglycerate
Mutase
Enolase
Pyruvate
Kinase
Lactate Dehydrogenase
G6P
Insulin,
Glucose
Glucagon,
F6P
-liver
-pancreatic B cells
-hi Km and Vmax
Fructose-2,6-
Bisphosphate
Phosphofructokinase-2
Fructose
Bisphosphatase-2
Insulin
Glucagon
F26BP is an
essential activator
of PFK-1
AMP
ATP, Citrate
ATP
Mg+2
Glucagon
is a binds to a TM receptor coupled to a trimeric G protein. Receptor changes conformation and favors the binding of GTP to the alpha subunit of the G protein. The activated G protein activates
Adenylyl Cyclase
which converts to
cAMP
. cAMP is an allosteric activator of
Protein Kinase A
, which in turn
phosphorylates protein targets
, such as the PFK2/FBPase2 complex.

A
high insulin/glucagon
ratio decreases cAMP levels.

In general:
-Insulin causes protein de-phosphorylation
-Glucagon causes protein phosphorylation
NADH
NAD+
NADH
NAD+
Electron
Transport
Chain
Pi
ATP
Mg+2
H2O
ATP
Mg+2
Insulin, F16BP
Glucagon, ATP, Ala
ATP
Mg+2
Anaerobiosis
Acetyl CoA
CO2
Pyruvate
Dehydrogenase
Lactate formation favored by
hi NADH/NAD+
ratio
LDH

direction also depends on
[pyruvate] and [lactate]
Glucose uptake by Na+ independent facilitated diffusion transport is mediated by a family of
GLUT transporters
.
GLUT1 --> RBCs and brain
GLUT3 --> neurons
GLUT4 --> adipose tissue and skeletal muscle
Insulin increases the expression of GLUT4
GLUT2
--> liver, kidney, B-cells...glucose
uptake OR release
Glucose uptake (against its conc. gradient) in the epithelial cells of the intestine, renal tubes, and chorid plexus requires co-transportation of Na (with its gradient).
-low Km (hi affinity)
-low Vmax
promotes transcription of the GK gene
causes GK to bind reg. prot. in nucleus
releases GK from reg. prot.
prevented by
hi F26BP
Remember:
2x per glucose from here on down
"substrate-level phosphorylation"
Feed-forward regulation
cAMP-dependent phosyl'n
--> PEP to gluconeogenesis
PK deficiency
(autosomal recessive) is second most common cause (after G6PDH def.) of enzyme-related
hemolytic anemia
restricted to RBCs
severe chronic HA requires regular cell transfusions
partially compensated for by increased production of 23BPG
Pyruvate
Carboxylase
CO2
TCA and FA synthesis
Oxaloacetate
Malate
Fumarate
Succinate
Succinyl Co-A
alpha-Ketoglutarate
Isocitrate
Citrate
Tri-Carboxylic
Acid Cycle

Citrate Synthase
Fumarase
Isocitrate
Dehydrogenase
Succinate
Dehydrogenase
Succinyl CoA
Synthetase
aKG Dehydrogenase
Complex
Aconitase
mitochondrial
Malate
Dehydrogenase
H2O
CoA-SH
CO2
NADH
CO2
NADH
CoA-SH
CoA-SH
GTP
FADH2
H2O
NADH
Cytosol
Mitochondrion
Pyruvate transporter
Pyruvate
NADH
NAD+
Co-A
NADH, ATP,
and Ac-CoA
Component enzymes: multiple copies of each in tight physical association
-pyruvate dehydrogenase, E1, decarboxylase -->

requires TPP
-dihydrolipoyl transacetylase, E2 -->

requires lipoic acid and Co-A
-Dihydrolipoly dehydrogenase, E3 -->

requires FAD and NAD+
Phosphoprotein phosphatase
-dephosphorylates E1 in presences of Ca+2
cAMP-independent protein kinase
-phosphorylates E1 in presence of Ac-CoA, ATP, NADH -PK inhibited by pyruvate (thereby activating E1)
NAD+
ATP
Malate
cytosolic
Malate
Dehydrogenase
Oxaloacetate
cytosolic
PEP Carboxykinase
Occurs in liver and kidney
Uses
biotin
as a coenzyme
Purposes:
-provide substrate for gluconeogenesis
-replenish TCA cycle intermediates
Muscle pyruvate carboxylase forms OAA only to replenish TCA
OAA cannot cross mitoch. membrane --> converted to malate
Ac-CoA
GTP
CO2
Fructose 1,6-
bisphosphatase
AMP
ATP
In liver and kidney
Pi
H2O
F26BP
inhibits
F16BPase
dephosphorylated form is active
phosphorylated form is active
Glucose 6-Phosphate
Translocase
Brings G6P across ER membrane
Only in liver and kidney
Cytosol
Endoplasmic reticulum
G6P
Glucose 6-Phosphatase
Glucose
Pi
Specific transporters
necessary
Glucagon
Increases PEPCK gene transcription
Decreases PEPCK gene transcription
Insulin
sever fasting hypoglycemia
normal glycogen structure
hepatorenomegaly
PDH Deficiency
-most common cause of congenital lactic acidosis
-pyruvate converted to lactate via LDH
-can cause damage to cerebral cortex, basal ganglia, and brainstem
-X-linked dominant (E1 gene)
ATP, NADH, Succinyl Co-A,
FA derivatives
Primary regulation by availability of substrate
Ac-CoA for FA synthesis
Inhibitor of PFK-1
(glycolysis)
Activator of Ac-CoA carboxylase
(FA synthesis)
Fluoroacetate
Ca+2, ADP
ATP, NADH
rate-limiting
Complex of three enzymes; very similar to PDH
-requires TPP, lipoic acid, FAD, NAD+, and CoA
Ca+2
ATP, GTP, NADH, succinyl-CoA
AA catabolism
urea cycle
purine synthesis
Phe and Tyr catabolism
transamination of Asp
Phe
Tyr
These carbons
are not released
during their first turn around the TCA
main stores in skeletal muscle and liver
ATP synthesis during
muscle contraction
maintain blood glucose during early stages of a fast
Phosphoglucomutase
a (1->4) glucose
oligosaccharide

UDP-Glucose
n+1 residues
UDP-glucose
pyrophosphorylase
UTP
PPi
2 Pi
Pyrophosphatase
H2O
glucose 1,6-bisphosphate intermediate
Glycogen synthase A
can only elongate already existing chains of glucose
makes 1->4 glycosidic linkages
Glycogenin
can serve as primer
amylo-a(1->4)->(1->6)-
transglucosidase
"branching enzyme"
Glycogen
phosphorylase A
G6P
in liver and muscle
G6P, ATP, Glucose
in liver
G6P, ATP
in muscle
Ca+2, AMP
in muscle
Glycogen (n-1)
and
cleavage of a(1->4) glycosidic bonds at non-reducing ends of glycogen chains
-glucose transferred to non-reducing end of chain (the end where the anomeric carbon of the terinal sugar is linked by a glycosidic bond to another compound)
non-reducing end
anomeric carbons
Glycogen
Debranching Enzyme
Debranching
Enzyme
transfers 3 residues of shortened branch
hydrolytic cleavage of
last residue [an a(1->6) bond] in a branch
Glucose
Glucose
Lysosomal a(1->4)
glucosidase

Affects liver, kidney, and intestine
Severe fasting hypoglycemia
Hepatomegaly (fatty liver)
Progressive renal disease
Growth retardation and delayed puberty
Hyperlacticacidemia and hyperuricemia
Normal glycogen structure; increased glycogen stored
Treatment: Nocturnal gastric infusions of glucose or regular administration of uncooked cornstarch

Inborn lysosomal enzyme deficiency
Generalized (primarily liver, heart, skeletal muscle)
Glycogen accumulates in lysosomes
Normal blood sugar levels
Massive cardiomegaly
Early death (<2 yrs) usually occurs from heart failure
Normal glycogen structure
"Pompe's trashes the pump [heart]"

Only skeletal muscle affected
Temporary weakness and cramping after exercise
No rise in blood lactate during strenuous exercise
Normal mental development
Myoglobinemia and myoglobinuria
Fair to good prognosis
High level of muscle glycogen w/ normal structure
Glycogen
Synthesis and Breakdown

Glycogen is
rapidly-mobilizable
Allows glucose
release from the liver and kidney
in the absence of dietary glucose
Muscle
glycogen is degraded in exercise to provide tissue with energy
When glycogen stores depleted, specific tissues synthesize glucose from amino acids
Ca+2 - calmodulin
complex binds to and
activates

physphorylase kinase
without the need for phosphorylation. Maximal activation when phosphorylated and bound to Ca/Calmodulin.
AMP
binds directly to muscle glycogen phosphorylase, causing
activation
without phosphorylation.
Glucose + glycogen phosphorylase B
can not be allosterically activated by AMP
Glucose + glycogen phosphorylase A
is better substrate for protein phosphatase 1 -->
glycogen degradation not required
Insulin
inhibits muscle glycogen phosphorylase by increasing uptake of glucose --> increase in
G6P levels
--> allosteric
inhibition
of glycogen phosphorylase
P
Inactive Glycogen
phosphorylase B
Phosphorylase
Kinase A (active)
P
Phosphorylase
Kinase B (inactive)
cAMP-dependent
Protein Kinase
Protein Phosphatase 1
Glucagon
Epinephrine
Protein phosphatase 1
ATP
ATP
Insulin
Insulin
Glycogen synthase B
(inactive)
P
cAMP-dependent
Protein Kinases
(A & C)
Glucagon
Epinephrine
Protein
Phosphatase 1
Insulin
Fructose
Fructose
1-Phosphate

Fructokinase
low affinity for fructose
liver, kidney, small intestine
ATP
Aldolase B
liver, kidney,
small intestine
Glyceraldehyde
Triokinase
ATP
Glycerol
Glycerol-P
Alcohol
Dehydrogenase
NADH
Glycerol
Kinase
ATP
Phosphoglycerides
Triacylglycerides
Hexokinase
ATP
Sucrose
in small intestine
Sucrase
Essential fructosuria
Lack of fructokinase
Autosomal recessive (1:130k births)
Benign, asymptomatic condition
Fructose accumulates in urine
Hereditary fructose intolerance
Absence of aldolase B --> intracellular trapping of F1P
Hypoglycemia, vomitting, jaundice, hemorrhage, hepatomegaly, and hyperuricemia
Can cause hepatic failure and death
Therapy: Rapid detection and removal of fructose and sucrose from the diet
Mannose
Mannose 6P
Hexokinase
Phosphomannose isomerase
ATP
Glucose
Sorbitol
Aldolase reductase
Found in: lens, retina, Schwann cells, liver, kidney, placenta, RBCs, ovaries, sperm, and seminal vesicles
Sorbitol dehydrogenase
Found in: liver, ovaries, sperm, and seminal vesicles
Why?
Sperm use fructose as major CHO energy
Liver can convert any available sorbitol to glycolytic intermediate
NADPH
NADPH
Sorbitol cannot pass efficiently through cell membranes, so when it is formed in hyperglycemic conditions (DM) with little or no sorbitol DHase (such as in the lens, retina, kidney, and nerve cells), it can cause swelling as a result of water retention. This can in turn result in catacact formation, peripheral neuropathy, and vascular problems associated with diabetes.
entry to cell is insulin-independent
Galactose
Galactose 1P
UDP-Galactose
Galactose 1P
uridyltransferase
Galactokinase
UDP-hexose
4-epimerase
Lactose
Glycoproteins
Glycolipids
Glycosaminoglycans
Lactose
Lactase
(B-galactosidase)
Galactitol
Aldolase reducatase
present in liver, kidney, retina, lens, nerve, seminal vesicles, and ovaries
physiologically unimportant unless galactose is high
elevated galactitol can cause cataracts
Galactokinase deficiency
Causes galactosemia and galactosuria
Causes galactitol accumulation if galactose present in diet
Classic galactosemia
Uridyltransferaes deficiency
Autosomal recessive (1:23k births)
Causes galactosemia and galactosuria, vomiting, diarrhea, and jaundice
Accumulation of Gal-1-P in nerve, lens, liver, and kidney tissue causes liver damage, severe mental retardation, and cataracts
Antenatal diagnosis is possible by chorionic villus sampling
Treatment: Rapid diagnosis and removal of galactose (therefore, lactose) from diet
synthesis in mammary glands
in intestinal mucosa cell membrane
G6Pase not found in muscle cells
consumes energy
Arginosuccinate
Arginine
Aspartate
Urea
Carbamoyl-P
Citrulline
NH3
Ornithine
CO2
glutamate
a-keto acid
a-amino acid
aminotransferases
transamination
-ALT forms pyruvate from Ala
-AST shuttles N from Glu to Asp
during AA catabolism (Asp to urea cycle)
all require pyridoxal phosphate
(deriv of vit B6)
Clinical correlation:
aminotransferases in blood indicate damage to cells.
-Liver disease: elevated plasma AST and ALT
-Other: myocardial infarction and muscle disorders
Glutamate dehydrogenase
oxidative deamination
NAD+ or
NADP+
NH3
NAD+ primarily used in oxidative deamination
NADPH used in reductive amination
ATP
GTP
ADP
GDP
Ammonia transfer to liver
-
Glutamine synthetase
in most tissues produces Gln which is transported in blood to liver, where glutaminase cleaves Gln producing Glu and NH3.
-
Transamination of pyruvate
in muscle forms alanine which is transported in blood to liver. Pyruvate produced in the liver can be converted to
glucose
through GNG.
2 ATP
Carbamoyl phosphate
synthetase I
N-acetyl-glutamate
absolutely required
Citrulline
Ornithine
Fumarate
Ornithine trans-
carbamoylase
Arginosuccinate
synthetase
ATP
AMP
Arginosuccinate
lyase
Arginase
Urea Cycle
Malate
Glutamate
Oxaloacetate
a-ketoglutarate
a-ketoglutarate
Pi
Glucose
To mitochondria and TCA via the malate shuttle
almost exclusively in the liver
to kidney via blood
Some urea diffuses from blood to
intestine
where bacterial
urease
cleaves it to CO2 and NH3.
-In patients with
kidney failure
, a greater amount of urea is transfered to the gut, and bacterial urease contributes significantly to hyperammonemia.
Neomycin
reduces the number of bacteria responsible for this NH3 production.
arginine
-2 per glucose
Malate
Glutamate
a-ketoglutarate
Aspartate
Oxaloacetate
Malate
Glutamate
a-ketoglutarate
Aspartate
Oxaloacetate
Mal-aKG antiporter
Glu-Asp antiporter
NADH
Malate dehydrogenase
NADH
Malate dehydrogenase
Aspartate aminotransferase
Aspartate aminotransferase
-via mal-asp shuttle
Malate-Aspartate Shuttle
-uses malate to carry NADH across mitochondrial membrane for use in the ETC
NADH
NADH
Hexose Monophosphate Shunt
Erythrose 4P
Ribulose 5P
6P Gluconate
Sedoheptulose 7P
Xylulose 5P
Glyceraldehyde 3P
Ribose 5P
6P Gluconolactone
6PG Hydrolase
Glucose 6-Phosphate
Dehydrogenase
NADPH
Insulin
NADPH
6PG DHase
NADPH
Reductive biosynthesis
Reduction of
hydrogen peroxide
-and other

reactive oxygen species

formed from the partial reduction of molec O2
-reactive intermediates can damage DNA, proteins, and unsaturated lipids
-RBCs are totally dependent on PPP to generate NADPH to maintain
glutathione
in its reduced form
Cytochrome P450
monooxygenase system
-reduces steroid, drug, and other chemicals in the mitochondria and SER
WBC Phagocytosis
-
MPO system
uses
NADPH oxidase

to consume oxygen in the phagolysosome and create a
"respiratory burst"
which kills ingested microbes
Synthesis of nitric oxide
-requires Arg, O2, and NADPH as substrates for

NO synthase
-NO is endogenous vasodilator; acts through guanylate cyclase
G6PD Deficiency
-characterized by
hemolytic anemia
caused by the inability to detoxify oxidizing agents
-
X-linked
family of deficiencies caused by >400 different mutations in G6PD gene (mostly point mutns)
-increased
resistance to malaria
in female carriers
-
most severe manifestation is in RBCs
, where PPP is required to obtain NADPH --> Heinz bodies; rigid and nondeformable RBCs which are removed by macrophages in spleen and liver
-
precipitating factors:
oxidant drugs (SMX, antimalarials, chloramphenicol); favism; infection; neonatal jaundice
Transketolases
and
Transaldolases

Glycolysis
and
Gluconeogenesis

thiamine
-dependent
Insulin, Ca+2,
ADP
rate-limiting step
NADH
hyperlipidemia
fasting lactic acidosis
nonresponsive to glucogneogenic stimuli
GSD Type I: von Gierke's
GSD Type Ib: G6P Translocase Deficiency
GSD Type II: Pompe's Disease
GSD Type III: Cori's Disease
fasting hypoglycemia (milder than Type I)
normal blood lactate levels
glycogen has short outer branches
glycogenolysis is defective; GNG is fine
hepatomegaly in infancy
GSD Type IV: Andersen's
accumulation of long, insoluble glycogen chains
hepatomegaly and cirrhosis
infantile cirrhosis and FTC --> usually fatal
GSD Type V: McArdle's Syndrome
defective hepatic glycogen phosphorylase
defective glycogenolysis, but GNG is fine
mild fasting hypoglycemia
normal glycogen structure
early childhood presentation of hepatomegaly may improve with age
GSD Type VI: Hers' Disease
occurs in the liver
Citrate
Acetyl CoA
Oxaloacetate
ATP-Citrate lyase
ATP, CoA
Malonyl CoA
two carbons
three carbons
acetyl CoA carboxylase
ATP
CO2
citrate
long-chain
fatty acyl-CoA
acetyl CoA carboxylase
P
cAMP-dependent PK
phosphorylation in presence of
glucagon and epinephrine
protein phosphatase
dephosphorylation in
presence of
insulin
(inactive dimer)
active polymer
high-calorie, high-CHO
diets also
cause an increase in Ac-CoA carboxylase
synthesis over the long-term
Acetyl CoA
Malonyl CoA
fatty acid
synthase

+2NADPH
Malonyl CoA
+2NADPH
CO2
CO2
palmitate
16C, saturated
each addition of mal-CoA requires
2NADPH
, produces
CO2
, and
elongates the fatty acid chain by

2Cs
fatty acid synthase

shuttles the growing chain
back and forth between an
acyl carrier protein
and the thiol group of a

cysteine residue
can be further elongated in the ER and mitoch
desaturation (addition of cis-DBs) in the ER
de novo
Fatty Acid Biosynthesis

NADH
cytosolic
PEP Carboxykinase
Glucagon
Increases PEPCK gene transcription
Decreases PEPCK gene transcription
Insulin
CO2
GTP
(negative regulator of PFK-1)
requires

biotin
Fatty acyl CoA
Dihydroxyacetone
Phosphate

Glycerol-P
Phosphotriose
Isomerase
Triacylglycerol
glycerol 3-P dehydrogenase
NADH
Glycerol
Fatty acid
R1 is typically
saturated
R2 is typically
unsaturated
R3 can be
either
in liver and adipose
glycerol kinase
in liver only
fatty acyl-CoA synthetase
ATP
AMP + PPi
CoA
ATP
acyltransferase
storage in adipose tissue
export from liver as VLDL
long-chain
Fatty acyl CoA

Carnitine palmitoyl-
transferase I
Fatty acyl
CoA
Carnitine palmitoyl-
transferase II
Carnitine
RCO-Carnitine
CoA
RCO-Carnitine
CoA
Fatty acyl CoA
Carnitine
aka CAT II
aka CAT I
malonyl-CoA
obtained from
diet
synth from
Lys and Met
short/med chain
Fatty acids

short/med chain
Fatty acids

3-ketoacyl CoA
Acetyl CoA
3-hydroxyacyl CoA
enoyl CoA
FADH2
H2O
NADH
CoA
Fatty
Acid
B-oxidation

Propionyl CoA
final step of
odd-chain
oxidation
only product that is
gluconeogenic
link to GNG:
Acetyl-CoA is
positive regulator
of
pyruvate carboxylase
acyl-CoA
dehydrogenases
autosomal recessive disorder
inability to oxidize FAs w/ <12 Cs
symptoms of hypoglycemia
Tx: avoid prolonged fasting;
CHO+, protein+, FA- diet
Med-chain FA CoA DH deficiency (MCADD)
(oxidation)
enoyl CoA hydratase
(hydration)
dehydrogenase
(2nd oxidation)
ACAT
ATP
CO2
biotin
Vit B12
HMG CoA Synthase
NADH
HMG CoA
Acetoacetate
3-Hydroxybutyrate
Acetone
Ketone Body Synthesis
occurs in
liver mitoch
acetoacetate and 3-hydroxybut transported to peripheral tissues where they are re-converted to Ac-CoA and
oxidized by the TCA
major source of energy
for peripheral tissues, including the brain (esp important during prolonged fasting)
Diabetic ketonuria
in
uncontrolled DM I
(insulin-dep), high FA
degrad'n -->
xs Ac-CoA
and slows TCA
xs Ac-CoA --> ketones -->

urinary excretion + fruity breath
elevated blood ketones

(more H+ in less volume)

-->
acidemia

-->
dehydration and ketoacidosis
Regulation
Fates
of
Pyruvate
In the presence of
arsenic
, G3P --> 3PG w/o forming NADH
2,3-BPG
BPG Mutase
esp in
RBCs
-> increases
Hb release
of O2
Full transcript