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Major pathway for glucose metabolism in all cells, nearly universal o Malate-Aspartate Shuttle
In cytosol, non-compartmentalized, primitive CYTOSOL MITOCHONDRIA
Sets the stage for complete oxidation of glucose into CO2 and H2O (via TCA: pyruvic acid to acetyl CoA) OAA ASP ASP OAA
Integrated into many other metabolic processes, with intermediates common to other pathways NADH NAD NAD NADH ETC
3 Types of Chemical Transformations Mal Mal
o Degradation of carbon skeleton of glucose to yield pyruvate o -glycerophosphate Shuttle
o Phosphorylation of ADP to ATP by high energy PO4 compounds CYTOSOL MITOCHONDRIA
o Transfer of H+ atoms or electrons to NAD NADH+H DHAP DHAP
Glycolytic intermediates are phosphorylated NADH NAD FAD FADH ETC
o PO4 negative charge at ph 7 traps intermediate in the cell -GP -GP
o PO4 groups essential for enzymatic conservation of energy Energetics
o PO4 binds to active site of enzymes providing binding energy to lower activation energy Aerobic: G + 2 Pi + 2 ADP 2 lactate + 2 ATP + 2 H2O;
Property Hexokinase Glucokinase o net of 2 ATP / G; @ oxygen debt or lacking mitochondria, no net NADH+H consumption
Tissue Distribution Most tissues Liver, pancreas Anaerobic: G+ 2Pi + 2 NAD + 2 ADP 2 pyruvate + 2 ATP + NADH + 2H+ + H2O;
Glucose Km Low (0.1mM) High (10mM) o net of 2 ATP / G; 2 NADH+H / G, NADH into ETC = 2 or3 ATP
Vmax Low High Reaction Moles ATP produced or consumed / mole G
Substrate specificity D-glucose, hexoses D-glucose only G G6P -1
Inhibition by G6P yes no F6P F1,6BP -1
Insulin induction no yes GA3P 1,3BPG +4/+6
Shuttle System: NADH+H not used in pyr reduction to lac transported across mitochondrial membrane 1,3BPG 3-PG +2
Reduction of organic molecule by NADH+H go to mito reoxidation with NAD in mito back to cytosol PEP Pyr +2
Net +2 (+6/+8 if aerobic)
Step Substrate Product Enzyme Action Stimulators / Activators Inhibitors / Deactivators Notes
Glucose Hexokinase, Effectively traps G Irreversible, 1st regulatory step, requires ATP with
Phosphorylation Glucose-6-phosphate (G6P) 2-deoxyglucose
(G) glucokinase inside the cell Mg2+
PREPARTORY STAGE
ensures complete oxidation of glucose to CO2 and H2O Anaplerotic Reactions: refill / replenish depleted intermediates in TCA which have been used for biosynthetic
in mitosol, amphibolic reactions; continuous functioning
provides intermediates for biosynthesis of other compounds o Carboxylation of pyruvate
final oxidative pathway for CHO, FA, AA Principal anaplerotic reaction, in mitochondria
oxidation of molecules accounts for greatest fraction(2/3) of O2 consumption and ATP production Catalyzed by pyruvate carboxylase, ATP-dependent, allosterically activated by aCoA and LCF
principal source of reducing equivalents that enter ETC acylCoA
Energetics: acetyl CoA + 3NAD + FAD + GDP + Pi + H2O 2CO2 + 3NADH + 3H+ + FADH2 + GTP + CoASH o Reductive carboxylation of pyruvate to malate
Reactions Moles ATP / Mole Pyr Moles ATP / Mole G In cytosol
Catalyzed by NADPH-linked malate enzyme (NOT identical to mitochondrial malate DH)
Pyr aCoA 3 (NADH) 6
Provides NADPH for FA synthesis
Ict oxalosuccinate / KG 3 (NADH) 6
o Transamination of aspartic acid to OAA
KG sCoA 3 (NADH) 6 o Transamination of glutamic acid to KG
sCoA suc 1 (ATP) 2 o Degradation of C skeletons of glucogenic AAs
Suc fum 2 (FADH2) 4 Met, Val, Ile sCoA
Mal OAA 3 (NADH) 6 Tyr, Phe Fum
Total 15 30 (+6/+8 from aerobic glycolysis)
Step Substrate Product Enzyme Action Stimulators / Activators Inhibitors / Deactivators Notes
Pyruvate dehydrogenase (PDH) enzyme Allosterically: AMP,
Oxidation Allosterically: ATP, acetyl
CoASH, NAD, Ca2+,
Preliminary Oxidation
pyruvate Acetyl CoA complex (E1-3); active when Links EMP to TCA Irreversible, in mitosol
(3 Steps) CoA, FA, NADH, high energy
dephosphorylated (kinase / phosphatase) low energy
Decarboxylation pyruvate Hydroxyethyl derivative E1: Pyruvate decarboxylase + TPP
Hydroxyethyl derivative /
Oxidation / Disulfide lipoic acid / E2: Dhidrolipoyl transacetylase + lipoic
Acetyl group as thioester
Transfer acetyl CoA acid
in lipoic acid
Oxidation / Sulfhydryl lipoic acid / Regenerated lipoic E3: Dihydrolipoyl DH + FAD, NAD,
Reoxidation FADH2 acid / FAD CoASH
Oxaloacetate (OAA), ATP, NADH, succinyl CoA, Rate-limiting / regulatory
Condensation Citrate (Cit) Citrate synthase Aldol condensation OAA, aCoA
acetyl CoA (aCoA) citrate, LCF acylCoA step
Isomerization Cit Isocitrate (ict) aconitase Dehydration, hydration Ca2+, ADP Fluorocitrate, ATP
Isocitrate, AMP, ADP,
Oxidation and Releases 1st of 3 NADH ATP, NADH, high energy Irreversible, rate-limiting
Ict -ketoglutarate (KG) Ict DH Ca2+, low energy
carboxylation and 1st CO2 charge step
charge
TCA Cycle
Hydrolysis
6PGL lactone group 6-phosphogluconic acid (6PGA) gluconolactonase
Oxidative decarboxylation
6PGA Ribulose-5-phosphate (Rbls5P) 6-Phosphogluconate DH (NADP-linked) Produces 2nd NADPH
Conversion
Rbls5P Ribose-5-phosphate (Rbs5P) Phosphopentose isomerase (ketoisomerase)
Non-Oxidative
(Isomerization)
Conversion Rbs5P Xylulose-5-phosphate (X5P) Phosphopentose epimerase
GA3P + sedoheptulose-7-phosphate
Transketolation 1 X5P + Rbs5P Transketolase Donor: Ketose, Receiver: Aldose
(S7P)
Transaldolation S7P + GA3P Erythrose-4-P (E4P) + F6P Transaldolase Donor: Aldose, Receiver: Ketose
Transketolation 2 X5P + E4P GA3P + F6P Transketolase
Synthesis of glucose from non-carb sources (lac, pyr, glycerol, glucogenic AA, odd-chain FA)
Both in cytosol and mitochondria in liver (90%) and renal cortex (10%)
Not a reverse of glycolysis/EMP; but 8 out of 11 glycolysis steps are reversible and are shared
o Direct reversal of EMP = G = +20 Kcal/mol = very unfavorable thermodynamically
o GNG = G = -9 Kcal/mol = feasible
4 unique rxns (pyruvate carboxylase (pyr CX), PEP CX, F1,6BP 1-phosphatase, and G6Pase) w/c circumvent the 3 irreversible glycolytic rxns (Hexokinase, PFK1, pyruvate kinase)
All inhibitors of EMP are activators of GNG and vice versa
Fxn: maintains blood sugar concentration, uses lactate and glycerol (end products of glycolysis and glycerol), excretes excess protons by kidneys during metabolic acidosis, recycles C skeletons of deaminated AA
Energetics: couples cleavage of cleavage of 6 high-energy phosphate bonds per glucose molecule
Reaction Change in ATP / Glucose
Pyr OAA -2 ATP
OAA PEP -2 GTP (or ATP)
3PGA 1,3BPG -2 ATP
Total -6 ATP
o Summary: 2 pyr + 4ATP + 2GTP + NADH +2H+ glucose + 2 NAD+ + 4ADP + 2GDP + 6Pi
Regulation
o Enzyme compartmentation pyr kinase (cytosol), pyr CX (mito)
o Substrate availability glucogenic AA and lactate
o Allosteric regulation and feedback control
Pyr CX by aCoA, ATP
Pyr kinase if inhibited directs to GNG; by F1,6BP; ATP, alanine, free FA, aCoA (high energy)
F1,6BP1Pase by citrate, ATP; by AMP, ADP, F2,6BP
G6Pase by Pi and glucose (product inhibition)
o Hormonal control
Induction of enzyme synthesis key GNG enzymes by glucocorticoids, by insulin (also induces EMP enzymes)
Covalent modification
Glucagon pyr kinase by phosphorylation, F2,6BPase by phosphorylation
Insulin GNG by cAMP levels = phosphorylation of F2,6BPase
synthesized and stored in cystolic granules in liver and muscle, higher conc in liver, greater % in muscle
polymeric nature easier sequestration of energy stores (unlike glucose)
liver glycogen maintains blood glucose via breakdown; 10% of weight is glycogen (higher in well-fed state), lasts 12-24 hours
muscle glycogen for fuel reserve; 2% weight as glycogen
GLYCOGENESIS (Synthesis)
Step Substrate Product Enzyme Notes / Action
Isomerization G6P Glucose-1-phosphate (G1P) Phosphoglucomutase
Formation G1P + UTP UDP-glucose (UDPG) + PPi UDPG pyrophosphorylase
Hydrolysis UPDG + PPi Pyrophosphatase
Formation Old glycogen fragment or glycogenin Glycogen primer Glycogen initiator synthase free G cannot accept a molecule of G from UDPG to initiate chain synthesis
Elongation via G from UDPG + primer Elongated primer with G, UDP Glycogen synthase (GlyS) Forms 14 glycosidic bonds,
Transfer
Branching 7G chain Connects to C6 Branching enzyme (-D-glucsyl-4:6 transferase / Forms 16 glycosidic bonds, irreversible, at least 11G before transfer (4G
oligo 1,41,6 glucantransferase) remains between branching), solubility, non-reducing ends = synthesis
GLYCOGENOLYSIS (Degradation)
Step Substrate Product Enzyme Notes / Action
Phosphorolysis Terminal 1,4 glycosidic bonds at G1P Glycogen phosphorylase Rate limiting step, ends if 4G remaining on chain before branch
non-reducing end
Debranching Glycogen chain Shorter branch Glucose 4:4 transferase Transfers outer 3G of 4G of a branch to non-reducing end of another chain
Glycogen chain G, glycogen chain Amylo 1,6 glucosidase Breaks 1,6 linkage, makes chain available for glycogen phosphorylase
Regulation
Enzyme Activity State (Phosphorylated/ Action/Notes
Dephosphorylated)
GlyS D Inactive P G6P dependent
GlyS I Active D G6P independent
Glycogenesis cAMP-dependent protein kinase Interconverts GlyS D/I
Phosphoprotein phospatase Dephosphorylates GlyS D
Phosphoprotein phospatase inhibitor Active/Inactive P/D
GlyP a Active P Liver: dimer with pyridoxal PO4; Muscle: allosterically activated by ATP, G6P ( energy)
GlyP b Inactive D By phosphatase; Muscle: allosterically activated by AMP ( energy)
Glycogenolysis
Phosphorylase kinase Active/Inactive P/D Activates GlyP b to a
cAMP-dependent protein kinase With cAMP activates phosphorylase, 2R/2C tetramer
Clinical Disorders
Hereditary Fructose Intolerance genetic deficiency of aldolase B = F1P = inhibits fructokinase, hepatic glycogen phosphorylase, aldolase A
Essential Fructosuria deficient hepatic fructokinase blood/urine fructose
Fructosemia deficient F1,6BP1P = F1,6BP in blood and urine
GALACTOSE METABOLISM
LACTOSE METABOLISM