Glycolysis and the Catabolism of Hexose
1. Glycolysis
Introduction
* D-Glucose
1. Major fuel
- complete oxidation (-2840 kJ/mol)
- storing glucose (starch and glycogen)
2. Central position in metabolism
- metabolic intermediates for biosynthetic
reaction
Glycolysis
1. Universal central pathway of glucose catabolism
2. Degraded in a series of enzymatic reactions to two pyruvate
3. Free energy is conserved in ATP and NADH
4. Sole source of metabolic energy
- erythrocytes, renal medulla, brain, sperm
Importance of Phosphorylated Intermediates
1. Negative charge at pH 7. Not diffuse out of the cells.
2. Conservation of metabolic energy
3. Binding energy
- binding of phosphate group to the enzymatic sites
- lowers activation energy and increase specificity
The Preparatory Phase of Glycolysis requires ATP
1. Two molecules of ATP are invested
2. Hexose chain is cleaved into two triose phosphate
1. Phosphorylation of Glucose
2. Conversion of Glucose 6-Phosphate to Fructose 6-Phosphate
3. Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-Bisphosphate
4. Cleavage of Fructose 1,6-Bisphosphate
5. Interconversion of the Triose Phosphates
The Payoff Phase of Glycolysis Produces ATP and NADH
1. Energy-conserving phosphorylation steps
- four molecules ATP, net yield of two molexules
- Two molecules of NADH
2. Two molecules of pyruvate
6. Oxidation of Glyceraldehyde 3-Phosphate to 1,3-Bisphosphoglycerate
7. Phosphorylation transfer from 1,3-Bisphosphoglycerate to ADP
The formation of ATP
1. Substrate-level phosphorylation
- involve soluble enzyme
- chemical intermediates
2. Respiration-linked phosphorylation
- involve membrane bound enzymes
- transmembrane gradients of protons
8. Conversion of 3-Phospgoglycerate to 2-Phosphoglycerate
9. Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate
10. Transfer of the Phosphoryl Group from Phosphoenolpyruvate to ADP(substrate phosphorylation)
Spontaneous conversion of Pyruvate
Glycolysis is under Tight regulation
* Pasteur effect
- the rate and the total amount of glucose consumption greater under anaerobic than aerobic conditions
- about 18 times glucose must be consumed anaerobically as aerobically
Glucose Catabolism Is deranged in Cancerous Tissue
Glucose uptake and glycolysis is 10 times faster in solid rumors
2. Overproduce several glycolytic enzymes
- hexokinase, insensitive by glucose 6-phosphate
3. p53 and ras are involved in the production of glycolytic enzymes in tumor cells
2. Fates of pyruvate under aerobic and anaerobic condition
Pyruvate is the Terminal Electron Acceptor in lactic Acid Fermentation
Lactate dehydrogenase (LDH)
- regenerated from NADH by the reduction of pyruvate to lactate
- dehydrogenation of the two molecules of glyceraldehyde 3-phosphate convert two molecules of NAD+ to two of NADH.
- prenicious anemia, myocradial infaction, liver disease, acute leukemia, widespread carvinoma
Ethanol is the Reduced Product in Alcohol Fermentation
1. First step
- pyruvate is decarboxylated in an irreversible reaction by pyruvate decarboxylase
*Pyruvate decarboxylase
- present in brewer's and baker's yeast
2. Second step
- acetaldehyde is reduced to ethanol through the action of alcohol dehydrogenase
Thiamine Pyrophosphate Carries 'Active Aldehyde' Group
1. A coenzyme derived from vitamin B1
2. Berberi
- swelling (accumulation of body fluids), pain, paralysis, ultimately death
3. Feeder pathways for glycolysis
Feeder Pathways for Glycolysis
Many carbohydrates besides glucose
- Storage polysaccharides: glycogen and starch
- Disaccharides: maltose, lactose, trehalose, and sucrose
- Monosaharides: fructose, mannose, and galactose
Glycogen and Starch Are Degraded by Phosphorolysis
1. Glycogen phosphorylase
- Phosphyrolysis and hydrolysis
- Pyridoxal phosphate is an essential cofactor
2. Phosphoglucomutase
Dietary polysaccharide and Disaccharide Are Hydrolyzed to Monosaccharides
1.Salivary -amylase (activated by lower pH)
- hydrolyzes the internal glycosidic linkage of starch
2. Pancreatic -amylase
- yiels mainly maltose and oligosaccharide
* Lactose intolerance
- large intestine Toxic products by bacteria
- abdominal cramps and diarrhea
4. Regulation of carbohydrate catabolism
Regulation of Carbohydrate Catabolism
1. ATP and a variety of precursor for biosynthetic processes
2. Glycogen phosphorylase
Hexokinase
PFK-1
Pyruvate kinase
Regulatory Enzymes Act as metabolic Valves
1. Homeostatis
2. Rate-limiting step
- Substrate-limited
- Enzyme-limited
3. Enzymes - exergonic, rate-limiting steps
- the targets of metabolic regulation
Glycolysis and Gluconeogenesis Are CoordinatelyRegulated
1. Seven of the glycolytic reactions are reversible
2. Three reactions are irreversible, exergonic
- hexokinase, PFK-1 and pyruvate kinase
Phosphofructokinase-1 Is under Complex Allosteric regulation
1.ATP
- a substrate of PFK-1 and end product of glycolysis (allosteric site)
2. ADP and AMP
- allsosterically relieve inhibition of ATP
3. Citrate
- a key intermediate in the aerobic oxidation of pyruvate
4. Fructose 2,6-bisphosphate
- the most significant allosteric regulator
Hexokinase is Allosterically Inhibited by Its Reaction Product
1. Hexokinase
- allosterically inhibited by glucose 6-phosphate
2. Liver hexokinase D (Glucokinase)
- Km of glucose is higher than the usual blood concentration
- Inhibited by glucose 6-phosphate and fructose 6-phosphate
Pyruvate kinase Is inhibited by ATP
- High concentrations of ATP
allosterically inhibite pyruvate kinase by decreasing its affinity for the phosphoenolpyruvate (PEP) substrate
- acetyl-CoA and long-chain fatty acid
(citric acid cycle intermediates)
Glycogen Phosphorylase Is regulated Allosterically and Hormonally
1.Muscle
- ATP production
- covalent modification, epinephrine
- Two allosteric modification, Ca2+ and AMP
2. Liver
- to maintain a constant level of blood glucose
- covalent modification, glucagon
- allosteric modification, glucose