Carbohydrate Catabolism I Chapter 14 and parts of 15 March 5, 2015 BC368 Biochemistry of the Cell II

Catabolism

Central Role of Glucose

Overview of glycolysis

Two phases of glycolysis

Preparatory Phase Fig 14-2

pg 526 Reaction 1: phosphorylation

Fig 14-3

 Tissue-specific isozymes. Hexokinase vs. glucokinase Fig 15-14

Reaction 2: isomerization aldose ketose

Reaction 2: isomerization Fig 14-3

Reaction 3: phosphorylation

Fig 14-3

Reaction 4: cleavage

Fig 14-3

Reaction 5: isomerization

Fig 14-3

Keeping Track of Carbons glucose G3P

Fig 14-2

Reaction 6: oxidation

Fig 14-3

Reaction 7: substrate level phosphorylation

Reaction 8: shift of phosphoryl group

Fig 14-3

~Fig 14-8 Fig 14-9

Reaction 9: dehydration

Reaction 10: substrate level phosphorylation

Energy investment Cleavage Energy Harvest Summary

Efficiency

Feeder Pathways Fig 14-9 glycerol Glycerol 3-P  All carbohydrate s enter glycolysis  In muscle, often via hexokinase

Case Study A 9-month-old is brought to your clinic with recurrent bouts of sweating and vomiting. Symptoms began shortly after weaning and introduction to solid foods. Testing reveals hypoglycemia and lactic acidosis after consumption of milk formula or fruit. Enzyme activity testing reveals a deficiency in fructose 1-phosphate aldolase. Notably, her 3-year-old brother has a marked aversion to fruit.

Fructose intolerance  Hereditary fructose intolerance results from a defect in fructose breakdown in the liver, usually in aldolase.

Glycogen Breakdown

Glycogen Phosphorylase  Glycogen phoshorylase catalyzes the simultaneous phosphorylation and cleavage of an  -1,4 linked glucose from a non-reducing end of glycogen.  This reaction is called “phosphorolysis.” Glycogen Breakdown

Fig Pyridoxal phosphate Glycogen Breakdown Step 1. Glycogen Phosphorylase Fig 14-12

Fig Glycogen Breakdown Phospho- glucomutase Fig 15-29

 G6P fate depends on tissue.  In muscle, G6P proceeds through glycolysis.  In liver, G6P is converted to glucose.

Limit Dextrins

Glycogen Breakdown Debranching enzyme Fig 15-28

Glycogen storage diseases

Fig Fate of the products, pyruvate and NADH Fig 14- 3

Fermentation in Animals

Lactic acid from skeletal muscle is sent into the bloodstream. Lactate threshold occurs when production exceeds clearance. Glycolysis cannot continue. Fermentation in Animals

Cori Cycle

Fermentation in Yeast

Pyruvate decarboxylase reaction

Alcohol dehydrogenase reaction

 Irreversible steps are regulated:  Hexokinase/Glucokinas e  Phosphofructokinase I  Pyruvate Kinase Regulation of glycolysis

 Tissue-specific isozymes. Glucose + ATP  G6P + ADP  Feedback inhibition by G6P. Control of Hexokinase

Control of PFK-1  Many allosteric effectors; e.g., ATP. H+,H+,

 ATP is an allosteric inhibitor of PFK- 1.  Two binding sites: substrate and allosteric site. Control of PFK-1

Control of pyruvate kinase PEP + ADP  pyruvate + ATP

Fig Control of pyruvate kinase

Control of glycogen phosphorylase phosphorylase b (inactive) phosphorylase a (active) phosphorylation glycogen breakdown

 Glycogen phosphorylase is activated upon phosphorylation by phosphorylase kinase.

 Phosphorylase kinase is activated upon phosphorylation by protein kinase A (PKA).  Glycogen phosphorylase is activated upon phosphorylation by phosphorylase kinase.

 PKA is activated by cyclic AMP, which is produced by a G-protein in response to epinephrine/glucagon.  Phosphorylase kinase is activated upon phosphorylation by protein kinase A (PKA).  Glycogen phosphorylase is activated upon phosphorylation by phosphorylase kinase.

Fig 14-1

Transketolase requires thiamine pyrophospate (TPP) as a coenzyme NADPH is necessary to protect against reactive oxygen species Ribose 5-P is necessary in rapidly dividing cells

Rxns 1 and 3 produce NADPH Rxn 4 produces ribose-5- phosphate Glucose 6-P + 2 NADP + + H 2 O  Ribose 5-P + 2 NADPH + 2 H + + CO 2 Oxidative phase From C1

Key Enzyme: G6P Dehydrogenase

Case Study Omar’s mother noticed that every time she served falafel, her son complained of feeling tired, hot, headachy, and sick to his stomach. At first she thought he was just being fussy, but sometimes he would actually look yellow. Medical testing confirmed hemolytic anemia. What’s up with Omar?  A deficiency in G6PDH is the most common human enzyme defect, affecting more than 400 million people worldwide. Protective against malaria. Divicine leads to reactive oxygen species Favism!

Case Study Omar’s mother noticed that every time she served falafel, her son complained of feeling tired, hot, headachy, and sick to his stomach. At first she thought he was just being fussy, but sometimes he would actually look yellow. Medical testing confirmed hemolytic anemia. What’s up with Omar? X

Regulation  G6P dehydrogenase is allosterically inhibited by NADPH; activated by NADP +

Glucose 6-P + 2 NADP + + H 2 O  Ribose 5-P + 2 NADPH + 2 H + + CO 2 Oxidative Phase  Some cells need NADPH but not ribose 5-P  Ribose 5-P can be recycled in the nonoxidative phase

Fig Fig Pentose Phosphate Pathway: Nonoxidative Phase

Carbon Shuffling Reactions Glucose 6-phosphate Ribose 5-phosphate Fig 14-23