Carbohydrate Metabolism Catabolism 2013
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Transcript of Carbohydrate Metabolism Catabolism 2013
CARBOHYDRATE CARBOHYDRATE MEMETABOLISMTABOLISMCATABOLISMCATABOLISM
EDITED BYEDITED BYLiniyanti D.Oswari,MD.,MNS,MSc.Liniyanti D.Oswari,MD.,MNS,MSc.
For Block For Block 88Medical student, Sriwijaya UniversityMedical student, Sriwijaya University
Carbohydrate MetabolismCarbohydrate Metabolism
GlycolysisGlycolysis2.3. Biphospoglycerate (2.3.BPG)2.3. Biphospoglycerate (2.3.BPG)GlycogenesisGlycogenesisGlycogenolysisGlycogenolysisHMP shuntHMP shuntGluconeogenesisGluconeogenesisREGULATION OF METABOLISM BY HORMONESREGULATION OF METABOLISM BY HORMONES
Carbohydrate Metabolism Carbohydrate Metabolism OverviewOverview glycogen
pentose GLUCOSE other sugars pyruvate
acetyl CoA EtOHlactate
TCA cycle ATP
Glucose UtilizationGlucose Utilization
Glucose
PyruvateRibose-5-phosphate
GlycogenEnergy Stores
Pentose Phosphate Pathway
Glycolysis
Adipose
GLYCOLYSISGLYCOLYSISGlucose can also be available from food intake. Glucose can also be available from food intake. Glucose is also stored as glycogen Glucose is also stored as glycogen
(glycogenesis).(glycogenesis).After After gluconeogenesis,gluconeogenesis, glucose is converted glucose is converted
from glycogen in liver or muscle from glycogen in liver or muscle for glycolysisfor glycolysis. . Glycolysis is the break down of a Glycolysis is the break down of a 6 C glucose 6 C glucose
sugar to two 3C pyruvate.sugar to two 3C pyruvate.
Central role of liver in metabolismCentral role of liver in metabolism
Glucose entering the hepatocyte is phosphorylated by Glucose entering the hepatocyte is phosphorylated by glucokinase to glucose-6-phosphate (G-6-P).glucokinase to glucose-6-phosphate (G-6-P).
Other monosaccharides are also made to G-6-P via Other monosaccharides are also made to G-6-P via gluconeogenesisgluconeogenesis, then glucose can be stored as , then glucose can be stored as glycogen. glycogen.
When we need energy, When we need energy, glycolysis glycolysis converts G-6-P to converts G-6-P to pyruvate and acetyl coA to enter Citric acid cycle to pyruvate and acetyl coA to enter Citric acid cycle to produce ATP energy via oxidative phosporylation produce ATP energy via oxidative phosporylation (aerobic metabolism).(aerobic metabolism).
Glycolysis: Glycolysis: break down of glucose in cytoplasmbreak down of glucose in cytoplasm
Glucose-6-phosphate
Glucose-1-phosphate
UDP-glucose
Glycogen
GlucoseHexokinase
Fructose-6-phosphate
Fructose-1, 6-biphosphate
Glyceraldehyde-3-phosphate
Dihydroxyacetone phosphate (DHAP)
Glycerol
Glyceraldehyde-1, 3-bisphosphate
Glycerate-3-phosphate
Glycerate-2-phosphate
Phospho-enol-pyruvate
NAD + Pi
NADH + H+
ATP
ATP
ADP
ADP H2O
H2O
Pyr
uva
teL
acta
te
Lac
tate
D
ehyd
rog
enas
e
ATPADP
ATPADP
ATPADP
Glycolysis: Phase 1 and 2• Phase 1: Sugar activation
– Two ATP molecules activate glucose into fructose-1,6-diphosphate
• The 1 and 6 indicate which carbon atom to which they are attached.
• Phase 2: Sugar cleavage (splitting) – Fructose-1,6-bisphosphate (6 C’s) is split into
two 3-carbon compounds:• Glyceraldehyde 3-phosphate (GAP)
Glycolysis: Phase 3• Phase 3: Oxidation and ATP formation
– The 3-carbon sugars are oxidized (reducing NAD+); i.e., 2 H’s + NAD NADH2
– Inorganic phosphate groups (Pi) are attached to each oxidized fragment
– The terminal phosphates are cleaved and captured by ADP to form four ATP molecules
– The final products are: • Two pyruvic acid molecules• Two NADH + H+ molecules (reduced NAD+)• A net gain of two ATP molecules
Glycolysis has two stagesGlycolysis has two stages..A. An energy investment phase. Reactions, 1-5. Glucose to two glyceraldehyde -3-phosphate molecules. 2 ATPs are invested.B. An energy payoff phase. Reactions 6-10. two glyceraldehyde 3-phosphate molecules to two pyruvate plus four ATP molecules.-- A net of two ATP molecules overallplus 2 NADH(10 ATP–2 ATP= 8 ATP).
GLYCOLYSIS GLYCOLYSIS Glucose ATP hexokinase ADP Glucose 6-phosphate phosphogluco- isomerase Fructose 6-phosphate ATPphosphofructokinase ADP Fructose 1.6-bisphosphate aldolase
triose phosphate isomerase Dihydroxyacetone Glyceraldehyde phosphate 3-phosphate
Glyceraldehyde 3-phosphateglyceraldehyde NAD+ + Pi
3-phosphate NADH + H+
dehydrogenase 1,3-Bisphosphoglycerate ADPphosphoglycerate kinase ATP 3-Phosphoglyceratephosphoglyceromutase 2-Phosphoglycerate enolase H2O Phosphoenolpyruvate ADP pyruvate kinase ATP Pyruvate
Three irreversible kinase reactionsprimarily drive glycolysis forward. hexokinase or glucokinase phosphofructokinase pyruvate kinase
These enzymes will be shown to beregulate glycolysis as well.
Hexokinase Vs Glucokinase
Hexokinase Glucokinase
Site Most tissues Hepatocytes
Islet cells (pancreas)
Kinetics Low Km
Low Vmax
High Km
High Vmax
Regulation G-6-phosphate F-6-phosphate
Insulin: Induction
Function Low glucose conc. High glucose conc.
Glucose sensor
-- REGULATION OF GLYCOLYSISREGULATION OF GLYCOLYSIS
1.1.HEXOKINASE and HEXOKINASE and GLUCOKINASEGLUCOKINASE
HEXOKINASEHEXOKINASE Commiting step in glycolysis:
phosphorylation of glucose. Inhibited by its product, glucose6-phosphate,
as a response to slowing of glycolysis . found in all cells of every organism low
specificity for monosaccharides (simple sugars) i.e., other monosaccharides can be phosphorylated by hexokinase. relatively high affinity for glucose, KM = 0.1 mM
GLUCOKINASEGLUCOKINASE liver enzyme with high KM (10 mM)for glucose so most effective when glucose levels are very high not inhibited by glucose 6-phosphatesensitive to high glucose in circulation from recent meal so it decreases high level of glucose in blood by taking glucose into liver
2. PHOSPHOFRUCTOKINASE PHOSPHOFRUCTOKINASE rate limiting for glycolysis an allosteric multimeric regulatory enzyme. Measures adequacy of energy levels.
Inhibitors: ATP and citrate high energy Activators: ADP, AMP, and fructose 2,6 bisphosphate low energy
ATP inhibits phosphofructoseactivity by decreasing fructose6-phosphate bindingAMP and ADP reverse ATP inhibition Fructose 2,6 bisphosphate is a very important regulator, controlling the relative flux of carbon through glycolysis versus gluconeogenesis.- It also couples these pathways to hormonal regulation.
3. PYRUVATE KINASEPYRUVATE KINASE PEP + ADP Pyruvate + ATP An allosteric tetramer -inhibitor: ATP & acetyl CoA & fatty acids (alternative fuels for TCA cycle)- activator: fructose 1,6-bisphosphate - (“feed-forward”) Phosphorylation (inactive form) anddephosphorylation (active form)under hormone control.Also highly regulated at the level of gene expression(“carbohydrate loading”)
Summary of Energy RelationshipsSummary of Energy Relationships for Glycolysis aerobicfor Glycolysis aerobic
Input = 2 ATP 1. glucose + ATP glucose-6-P 2. fructose-6-P + ATP fructose 1,6 bisphosphateOutput = 4 ATP + 2 NADH1. 2 glyceraldehyde-3-P + 2 Pi + 2 NAD+ 2 (1,3 bisphosphoglycerate) + 2 NADH2. 2 (1,3 bisphosphoglycerate) + 2 ADP 2 (3-P-glycerate) + 2 ATP3. 2 PEP + 2 ADP 2 pyruvate + 2 ATPNet = 2 ATP and 2 NADH( 8 ATP)
Energy Yield From GlycolysisEnergy Yield From Glycolysis
glucose 6 CO2 = -2840 kJ/mole
2 ATPs produced = 2 x 30.5 = 61 kJ/mole glucose Energy yield = 61/2840 = 2% recovered as ATP- subsequent oxidation of pyruvate and NADH can recover more of the free energy from glucose.
Carbohydrate Metabolism Primarily glucose
Fructose and galactose enter the pathways at various points
All cells can utilize glucose for energy production Glucose uptake from blood to cells usually mediated by insulin
and transporters
Liver is central site for carbohydrate metabolism Glucose uptake independent of insulin The only exporter of glucose
Blood Glucose Homeostasis Several cell types prefer glucose as energy
source (ex., CNS) 70-110 mg/dl is normal range of fasting blood glucose Uses of glucose:
Energy source for cells Muscle glycogen Fat synthesis if in excess of needs
Fates of Glucose
Fed state Storage as glycogen
Liver Skeletal muscle
Storage as lipids Adipose tissue
Fasted state Metabolized for energy New glucose synthesized
Synthesis and breakdown occur
at all times regardless of
state...
The relative rates of synthesis and
breakdown change
Synthesis and breakdown occur
at all times regardless of
state...
The relative rates of synthesis and
breakdown change
High Blood Glucose
Glucose absorbed
Insulin
Pancreas
Muscle
Adipose Cells
Glycogen
Glucose absorbed
Glucose absorbed
immediately after eating a meal…
Glucose Metabolism Four major metabolic pathways:
Energy status (ATP) of body regulates which pathway gets energy
Same in ruminants and non-ruminants
Immediate source of energy Pentophosphate pathway Glycogen synthesis in liver/muscle Precursor for triacylglycerol synthesis
Fate of Absorbed Glucose 1st Priority: glycogen storage
Stored in muscle and liver 2nd Priority: provide energy
Oxidized to ATP 3rd Priority: stored as fat
Only excess glucose Stored as triglycerides in adipose
Pyruvate Metabolism Three fates of pyruvate:
Conversion to lactate (anaerobic) Conversion to alanine (amino acid) Entry into the TCA cycle via pyruvate dehydrogenase pathway (create ATP)
Fate of Product of Glycolysis- Fate of Product of Glycolysis- PyruvatePyruvate- Pyruvate is at a central branch point in metabolism. Recall: Aerobic pathway - through citric acid cycle and respiration; this pathway yields far more energy and will be discussed later.
NADH + O2 NAD+ + energyPyruvate + O2 3CO2 + energy
Two Two anerobicanerobic pathways: pathways:
- to lactate via lactate dehydrogenase - to ethanol via ethanol dehydrogenase
- Note: both use up NADH produced so only 2 ATP per glucose consumed
Pyruvate metabolism
Convert to alanine and export to blood
COO–
C O
CH3
COO–
HC NH3+
CH3Alanine amino transferase
(AAT)
AlaninePyruvate
Glutamate -Ketoglutarate
Keto acid Amino acid
Pyruvate Dehydrogenase Complex (PDH) Prepares pyruvate to enter the TCA cycle
Electron Transport Chain
TCA Cycle
Aerobic Conditions
1. Lactate FermentationLactate Fermentation Enzyme = Lactate Dehydrogenase COO- COO-
C=O + NADH + H+ H-C-OH + NAD+
CH3 CH3
pyruvate lactate
-Note: uses up all the NADH(reducing equivalents) produced in glycolysis.
Helps drive glycolysis by using up NADH reversible so pyruvate can beregenerated in alternative metabolism lactate fermentation important in red blood cells, parts of the retina, and in skeletal muscle cells during strenuous exercise.-Also important in plants and in microbes growing in absence of O2.
-- Lactate Dehydrogenase (LDH) hasmultiple forms. It is an isozyme.Two polypeptides M and H cometogether to form LDH. It is a tetramerso a mixture is formed:M4, M3H, M2H2, MH3 and H4
M M M H H H H H H H M M M M M M M H H H
Skeletal muscle and liver containpredominantly the “MM” forms;heart the “HH” forms. During andafter myocardialinfarction (heartattack), heartcells die releasingLDH into thecirculation.
Diagnostic.
LACTIC ACID (CORI) CYCLELACTIC ACID (CORI) CYCLE glucose glucose glucose glucose-6-P glucose-6-P glycogen glycogen ATP ATP NADH BloodBlood NADH pyruvate pyruvate lactate lactate lactate LiverLiver MuscleMuscle
The liver uses most of this lactate tomake glycogen. Only small amountsof free glucose released.
Glycogen can be broken down intoglucose when needed.
2.2.Alcoholic FermentationAlcoholic Fermentation
COO- CO2 CH2OH H O
C=O C + NADH CH3 +CH3 CH3 NAD+
pyruvate acetaldehyde ethanol pyruvate decarboxylase- irreversible alcohol dehydrogenase- reversibleNote: NADH used up
- pathway is active in yeast.- second step helps drive glycolysis-second step is reversible- reverse is ethanol oxidation, eventially yields acetate, which ultimately goes into fat synthesis.- ethanol acetaldehyde acetate - humans have alcohol dehydrogenase in liver which mainly disposes of ethanol.- acetaldehyde is reactive and toxic.
SummarySummary GlucoseGlucoseoof Reactionsf Reactions 2 ATP 2 NADH 2 pyruvate2 NADH 2 NADHaanaerobic naerobic anaerobicanaerobic 2 ethanol + CO2 2 lactate
2 acetyl CoA + 2 CO2
O2 aerobicaerobic 4 CO2 + 4 H2O
The rate of Glycolysis will influent the affinity oxygen and Hemoglobine,with the intermediate 2,3 BPG pathway
Disorder in glycolysis will influent the affinity hemoglobine and oxygen.
Defficiency Piruvat kinase, so the level of 2.3 BPG will increase.
The affinity of oxygen and hemoglobine loose, and hypoxia in the tissue
Anemia hemolytic.
Deficiency Hexokinase - Genetic disease
- 2.3 BPG in RBC low - Affinity Hb and Oxygen is very strong
(abnormal) - Hypoxia in the tissue
Defficiency Piruvate kinase(Anemia Hemolitik)
- Blockade The end of glycolytic pathway, The affinity of oxygen and Hb decrease. turun.
- The production of ATP is not enough, so it decrease the activity of Na+ & K+, stimulate ion ATP ase pump.
It will keep the membran cell of RBC. Defficiency Piruvate Kinase will make RBC
Lysis.
The important pathways of glucose metabolism. Note that the glycogen degradations pathways end in -lysis, while the glycogen synthesis pathways end with -genesis.
Glycogenesis
Glycogen synthesis Occurs in cytosol of liver,muscle& kidney Occurs when blood glucose levels are high Excess glucose is stored (limited capacity)
liver and muscle are major glycogen storage sites liver glycogen used to regulate blood glucose levels brain cells cannot live for > 5 minutes without glucose muscle glycogen used to fuel an active muscle
Glycogen Synthesis Glucose units are activated for transfer by formation
of sugar nucleotides What are other examples of "activation"?
acetyl-CoA, biotin, THF, Leloir showed in the 1950s that glycogen synthesis
depends on sugar nucleotides UDP-glucose pyrophosphorylase - Fig. 23.18
a phosphoanhydride exchange driven by pyrophosphate hydrolysis
Glycogen Synthase Forms alfa-(1 4) glycosidic bonds in glycogen
Glycogenin (a protein!) forms the core of a glycogen particle
First glucose is linked to a tyrosine -OH Glycogen synthase transfers glucosyl units from
UDP-glucose to C-4 hydroxyl at a nonreducing end of a glycogen strand.
Note another oxonium ion intermediate
Control of Glycogen Metabolism
A highly regulated process, involving reciprocal control of glycogen phosphorylase and glycogen
synthase GP allosterically activated by AMP and inhibited
by ATP, glucose-6-P and caffeine GS is stimulated by glucose-6-P Both enzymes are regulated by covalent
modification - phosphorylation
Phosphorylation of GP and GS Covalent control
Edwin Krebs and Edmond Fisher showed in 1956 that a "converting enzyme" converted phosphorylase b to phosphorylase a(P)
Phosphorylation causes the amino terminus of the protein (res 10-22) to swing through 120 degrees, moving into the subunit interface and moving Ser-14 by more than 3.6 nm
Nine Ser residues on GS are phosphorylated!
Enzyme Cascades and GP/GS Hormonal regulation
Hormones (glucagon, epinephrine) activate adenylyl cyclase
cAMP activates kinases and phosphatases that control the phosphorylation of GP and GS
GTP-binding proteins (G proteins) mediate the communication between hormone receptor and adenylyl cyclase
Hormonal Regulation of Glycogen Synthesis and Degradation
Insulin is secreted from the pancreas (to liver) in response to an increase in blood glucose
Note that the portal vein is the only vein in the body that feeds an organ!
Insulin stimulates glycogen synthesis and inhibits glycogen breakdown
Note other effects of insulin
Hormonal Regulation II Glucagon and epinephrine
Glucagon and epinephrine stimulate glycogen breakdown - opposite effect of insulin!
Glucagon (29 res) is also secreted by pancreas Glucagon acts in liver and adipose tissue only! Epinephrine (adrenaline) is released from adrenal
glands Epinephrine acts on liver and muscles The phosphorylase cascade amplifies the signal!
O
O
OO
-[1- 4] linkages
O
O
O
O
O
O
O -[1-6] linkage
O ........
CH2OH CH2OH
CH2OH CH2OH CH2CH2OH
. The glycogen structure showing the glycosidic bonds
O
Liver 7–10% of wet weight Use glycogen to export glucose to the bloodstream when
blood sugar is low Glycogen stores are depleted after proximately 24 hrs of
fasting (in humans) De novo synthesis of glucose for glycogen
Skeletal muscle 1% of wet weight
More muscle than liver, therefore more glycogen in muscle, overall Use glycogen (i.e., glucose) for energy only (no export of
glucose to blood) Use already-made glucose for synthesis of glycogen
Glycogenesis
Pathway of glycogen synthesis (glycogenesis).
Glucose
Glucose-6-phosphate
Hexokinase(muscle)Glucokinase(liver)
ADP
UTP PPi
UDP-glucose
Glucose-1-PUridyltransferase
Glucose-1-phosphate
Phospho-glucomutase
ATP
UDP
(Glucose)n
(Glucose)n+
1
Glycogen Synthase
Glycogen synthesisGlucose 6-P→ glucose 1-P.glucose 1-P + UTP→UDP-glucose + PPi.PPi + H2O→ 2 Pi.UDP-glucose + glycogenn → glycogenn+1.
UDP + ATP → UTP + ADP.
Glucose 6-P + ATP + glycogenn + H2O →glycogenn+1 + ADP + 2Pi.
(nucleoside diphosphokinase)
Only one ATP is used to store one glucose residue in glycogen.
Glycogen synthesis and breakdown are reciprocally regulated
Red=inactive forms, green = active forms.
Protein phosphatase 1 (PP1) regulates glycogen metabolism.
InactiveActive
Glycogenolysis Glycogen degradation Occurs in cytosol Signal that glucose is needed is given by
hormones epinephrine stimulates glycogen breakdown in
muscle glucagon which stimulates glycogen breakdown
in liver in response to low BG used to sustain blood glucose level between meals
and to provide energy during an emergency/exercise
Glycogen Catabolism Getting glucose from storage (or diet)
-Amylase is an endoglycosidase It cleaves amylopectin or glycogen to maltose,
maltotriose and other small oligosaccharides It is active on either side of a branch point, but
activity is reduced near the branch points Debranching enzyme cleaves "limit dextrins" Note the 2 activities of the debranching enzyme
Glycogen
X glycolysis
LIVER PATHWAY
Glycogenolysis and the fate of glycogen in liver and kidney
Pi
glycogenphosphorylase
Glucose-1-phosphate
phosphoglucomutase
Glucose-6-phosphate
(inhibited by lack of fructose-2,6-bisP
glucose-6-phosphataseGlucose
Pi
. Glycogenolysis and the fate of glycogen in muscle.
lactate dehydrogenaseLactate
anaerobic
pyruvatedehydrogenase
Acetyl CoA
MUSCLE PATHWAYGlycogen
Pi
glycogenphosphorylase
phosphoglucomutase
Glucose-1-phosphate
Glucose-6-phosphate
glycolysis
Pyruvate
CO2
citric acid cycle
aerobic
Glikogenesis & Glikogenolisis Glucose anabolism
Glucose storage: glycogenesis glycogen formation is
stimulated by insulin glucose not needed
immediately is stored in the liver (25%) and in skeletal muscle (75%)
Glucose release: glycogenolysis converts glycogen to
glucose occurs between meals,
stimulated by glucagon and epinephrine
SIMPLISTIC SUMMARY:SIMPLISTIC SUMMARY:-- Epinephrine and glucagon stimulate glycogenolysis & inhibit glycogenesis via a cAMP and a phosphorylation cascade. release glucose-- Glycogenesis is stimulated by insulin in a pathway ending in the dephosphorylation of glycogen synthase.-- Glycogenolysis is also inhibited via dephosphorylation. take up glucose
Glycogen Storage Diseases:Glycogen Storage Diseases: A family of serious, although notnecessarily fatal, diseases caused bymutations in the enzymes involvingin glycogen storage and breakdown.
Glycogen Storage Diseases
Type I: Von Gierke Disease; Glucose-6-phosphatase Defect
Hypoglycemia occurs due to defect of the final step of gluconeogenesis. This disease, affects only liver and renal tubule cells Decreased mobilization of glycogen produces hepatomegaly. Decreased gluconeogenesis causes increased lactate leading to lactic acidemia.
Type V: McArdle Disease; Skeletal Muscle Glycogen Phosphorylase Defect
Skeletal muscle is affected, whereas the liver enzyme is normal. Temporary weakness and cramping of skeletal muscle occurs after exercise. There is no rise in blood lactate during strenuous exercise. Muscle contains a high level of glycogen with normal structure
Type VI: Hers Disease; Liver Glycogen Phosphorylase Defect
Liver is affected, whereas the skeletal muscle enzyme is normal. Marked hepatomegaly occurs due to a high level of glycogen with normal structure.. Following administration of glucagon, there is no increase in blood glucose.
Pentose Phosphate Pathway=Hexose Monophosphat Shunt
Generation of NADPH and Pentoses
Has 2 functions1.Generate reducing equivalents NADPH (reduced cosubstrate/ coenzyme) needed for fatty acid synthesis, folate reduction2. Produce ribose 5-phosphate needed for DNA and RNA synthesis
Occurs in cytosol of cells particularly important in anabolic tissues,liver, adrenal cortex, mammary glands and fat tissues
muscle cells do NOT have HMS enzymes
Pentose Phosphate Pathway
Glucose-6-phosphate
6-Phospho- glucono-lactone
6-Phospho- gluconate
D-Ribulose-5-phosphate
D-Ribose- 5-phosphate
RNA or DNA
A scenario in which the cell requires NADPH but does not require ribose-5-P
NADPH is used for biosynthetic reactions and glutathione metabolism
Glucose-6-P-dehydrogenase
Glucose Glucose 6-P
ATP ADP
6-Phosphogluconate
NADP NADPH
Ribulose 5-PCO2
NADPH
NADP6-Pgluconate dehydrogenase
Oxidative branch
Xylulose 5-P Ribose 5-P (5 carbons)
Sedoheptulose 7-P (7 carbons)
Erythrose 4-P
Transketolase
Transaldolase
Glyceraldehyde 3-P
Fructose 6-P
Fructose 6-P
TDP
TDP
Tra
nsk
eto
lase
Non
-oxi
dati
ve b
ranc
h
Glyceraldehyde 3-P
Glyceraldehyde-3-P and fructose-6-P return to the glycolytic pathway
Ribulose 5-P
Xylulose 5-P Ribose 5-P (5 carbons)
Sedoheptulose 7-P (7 carbons)
Erythrose 4-P
Transketolase
Transaldolase
Glyceraldehyde 3-P
Fructose 6-PFructose 6-P
Glyceraldehyde 3-P
TDP
TDPT
ran
sket
ola
se
A scenario in which the cell requires ribose-5-P but does not require NADPH
Ribose-5-P is the sugar required for the synthesis of nucleic acids
Oxidative branch is feedback inhibited by excess NADPH at glucose-6-P dehydrogenase
Nucleic acids
Glucose Glucose 6-P
Ribulose 5-P
6-Phosphogluconate
Ribose 5-P (5 carbons)
ATP ADP NADP NADPH
CO2
NADPH
NADP
Glucose-6-P-dehydrogenase
6-Pgluconate dehydrogenase
A scenario in which the cell requires both NADPH and ribose-5-P
Nucleic acids
Overview Function
NADPH production Reducing power
carrier Synthetic pathways
Role as cellular antioxidants
Ribose synthesis Nucleic acids and
nucleotides
Characteristics: Tissue Distribution Demand for NADPH
Biosynthetic pathways FA synthesis (liver, adipose, mammary) Cholesterol synthesis (liver) Steroid hormone synthesis (adrenal, ovaries, testes)
Detoxification (Cytochrome P-450 System) – liver Reduced glutathione as an antioxidant (RBC) Generation of superoxide (neutrophils)
Characteristics:Oxidative and Non-oxidative Phases
Oxidative phases Reactions producing
NADPH Irreversible
Non-oxidative phases Produces ribose-5-P Reversible reactions feed
to glycolysis
Regulation Glucose-6-P dehydrogenase
First step Rate limiting
Allosteric Regulation Feedback inhibited by NADPH
Inducible enzyme Induced by insulin
HMS ( Hexose Monophospat Shunt) Nicotinamide adenine dinucleotide phosphate
phosphorylated form of reduced nicotinamide adenine dinucleotide (NADH)
generated in a series of reactions comprising the oxidation-reduction phase of HMS
Ribose 5-phosphate sugar used as the backbone of DNA and RNA
Cell’s requirement for ATP (glycolysis) or NADPH and ribose 5-P (HMS) determines which path it will take.
Stages of HMS Reactions occur in 3 main stages
oxidation-reduction generation of NADPH
isomerization stage generation of ribose 5-phosphate
carbon bond cleavage-rearrangement stage conversion of three 5-carbon sugars to two 6-carbon sugars
(Fructose 6-phosphate) and one 3-carbon sugar (Glyceraldehyde 3-phosphate)
these series of reactions occur in cells where demand for NADPH is high F 6 P can be converted back to G 6 P which can re-enter HMS
Reactions of Stages 1 and 2
G6P is oxidized to 6-phosphoglucono-lactone by G6P dehydrogenase that uses NADP as coenzyme produces NADPH and 6-phosphoglucono
6-phosphoglucono is hydrolyzed (addition of water) to 6-phosphogluconate
6-phosphogluconate is oxidized by 6 phosphogluconate dehydrogenase produces NADPH and ribulose 5 phosphate
Ribulose 5-phosphate is isomerized to ribose 5 phosphate
Regulation of Metabolism Revisited
Allosteric Enzyme Modulation enzymes can be stimulated or inhibited by certain
compounds modulators act by altering conformational
structure of their allosteric enzymes causes shifts between relaxed and tight conformations
relaxed is most active
ratio of ADP (or AMP) to ATP is important in regulation of energy metabolism
Allosteric Enzyme Modulation low ADP:ATP ratio signals less need to
produce ATP inhibition of key enzymes in glycolysis and the
TCA cycle PFK, PDH, CS, and isocitrate dehydrogenase
high ADP:ATP ratio signals need for ATP activation of the above enzymes
ATP is end product in oxidative catabolism and its accumulation would signal to decrease catabolic pathway activity
Allosteric Enzyme Modulation
ratio of NADH to NAD+ is also important in regulation NADH is end product of catabolic pathway accumulation would signal to decrease activity diminution would signal to increase activity key enzymes are affected in glycolytic and TCA
cycle PK, PDH, CS, isocitrate dehydrogenase and alpha KG
dehydrogenase
Role of NADPH in the RBC Production of superoxide
Hb-Fe2+-O2 -> Hb-Fe3+ + O2-.
Spontaneous rxn, 1% per hour
O2-. + 2H2O -> 2H2O2
Both O2-. & H2O2 can produce reactive free
radical species, damage cell membranes, and cause hemolysis