Carbohydrate metabolism

Carbohydrate metabolism

Topics in Metabolism Carbohydrate metabolism
Overview of glucose homeostasis Glucose metabolic pathways and their regulation Glycolysis Citric acid cycle Gluconeogenesis Glycogen metabolism Pentose phosphate pathway Glucose Insulin Glycogen Lactate CO2 + H2O Fat Glucose

Carbohydrates Carbohydrates are called carbohydrates because they are essentially hydrates of carbon (i.e. they are composed of carbon and water and have a composition of (CH2O)n. The major nutritional role of carbohydrates is to provide energy and digestible carbohydrates provide 4 kilocalories per gram. No single carbohydrate is essential, but carbohydrates do participate in many required functions in the body.

Clinical example R.D., a 6-week-old girl, was born after a normal pregnancy and weighed 3.2 kg at birth . Her parents and two older siblings were in good health. She was breast fed for 4 wk, and her weight gain had been normal. At 4 wk of age, breastfeeding was discontinued and a common baby formula was substituted. As a result of poor initial formula preparation, the child develop a viral gastroenteritis and after several days exhibited fussiness, watery diarrhea, and vomiting. At age of 6 wk she was admitted to the hospital. Urinalysis yielded a +1 reaction for reducing substance.

Pediatric gastroenteritis
Was there any significant difference between the breast milk and the baby formulas? How did the gastroenteritis affect the digestion of carbohydrates? was the gastroenteritis related to diarrhea? What might have caused the explosive, acid, watery stool containing reducing substances?

Digestion Pre-stomach – Salivary amylase : a 1-4 endoglycosidase
a Limit dextrins G G G G G G G G G amylase G G G G Key- We must breakdown these very large oligosaccharides into monosaccharides in order to absorb them. Alpha amylase. – Cannot attack a1-4 linkase close to 1-6 branch points. G G a 1-6 link G G G G maltotriose G G a 1-4 link G G G G G G maltose G G isomaltose

Stomach Not much carbohydrate digestion
Acid and pepsin to unfold proteins Ruminants have forestomachs with extensive microbial populations to breakdown and anaerobically ferment feed

Small Intestine + Pancreatic enzymes a-amylase a amylase maltotriose
maltose + G G G G G G G G G G a amylase amylose G G G G G G G G G G G G G G G G G amylopectin a Limit dextrins

Oligosaccharide digestion..cont
a Limit dextrins G G G G sucrase G G G G G maltase G G Glucoamylase (maltase) or a-dextrinase G G G Maltase – specifically removes a single glucose from the nonreducing end of a linear a1-4 glucose chain…breaking down maltose into glucose. (exosaccharidases) Alpha dextinase – cleaves 1,6-alpha glucosidic linkages a-dextrinase G G G G G G G G G G G

Small intestine Portal for transport of virtually all nutrients
Water and electrolyte balance Enzymes associated with intestinal surface membranes Sucrase a dextrinase Glucoamylase (maltase) Lactase peptidases

Carbohydrate absorption
Hexose transporter Monosaccharides are still too large for passive diffusion across brush border membrane. We use facilitated diffusion to absorb these molecules. Glucose and galactose use a sodium-glucose symport (SGLUT1) while fructose uses the glut5 We must transport Na out of the cell to maintain proper electrochemical gradient (sodium potassium pump) Water will also follow sodium into enterocyte. This is critical to maintain proper water balance. apical basolateral

Carbohydrate malabsorption
Lactose intolerance (hypolactasia). Decline lactase with age Lactose fermented in LI – Gas and volatile FA Water retention – diarrhea/bloating Not all populations Northern European – low incidence Asian/African Americans – High b 1-4 linkage

Glucose metabolism: Breakfast
Eat cereal, bread, skimmed milk, fruit - mixture of monosaccharides (glucose, fructose), disaccharides (lactose, sucrose), complex carbohydrates (starch). Carbohydrates are broken down to monosaccharides for absorption in the small intestine. Glucose enters circulation through portal vein and increased blood glucose is detected 15 min after and peaking at min after meal hrs

Efficiency of glucose disposition after a meal
The amount of glucose in a meal (~100 g) is enough to raise the blood glucose level 8-fold, but in a healthy person, glucose level rises only 60%! Insulin level exhibits a much greater increase, from 60 to pmol/l (6-8-fold!). By the end of the post-absorptive period (~5 hrs), about 25 g of the carbohydrate ingested will have been stored as glycogen, and 75 g oxidized.

Blood glucose levels are relatively constant
8 am 6 pm noon midnight 2 4 6 8 Insulin 100 200 300 400 500 Glucose Plasma glucose (mmol/l) Plasma insulin (pmol/l) meals Time of day

Breakfast: Action of glucose in the b-cell
before meal after meal Insulin secretion is stimulated as the glucose concentration rises above 5 mmol/l (the normal baseline concentration of glucose in the plasma).

+ Breakfast: Fate of glucose in muscle Insulin GLUT4 Glucose Glucose
Hexokinase Glucose-6-P Glycogen synthesis Glycolysis

+ + - Breakfast: Fate of glucose in adipocytes Lipoproteins Insulin
LPL + GLUT4 Glucose Fatty acids Glucose Hexokinase Glucose-6-P Insulin - Glycerol-3-P Triglycerides

GLUT4 activity is regulated by insulin-dependent translocation
Intracellular pool of GLUT4 in membranous vesicles translocate to the cell membrane when insulin binds to its receptor. The presence of more receptors increases the Vmax for glucose uptake (does not affect Km). When insulin signal is withdrawn, GLUT4 proteins return to their intracellular pool. GLUT4 is present in muscle and adipose tissue.

Control of blood glucose requires cooperation between organs
liver liver Glycogen Food consumption Gluconeogenesis Glucose muscle adipocytes liver

Definitions: Catabolism = the breakdown of complex substances.
************************************************************ Definitions: Catabolism = the breakdown of complex substances. Anabolism = the synthesis of complex substances from simpler ones. ***********************************************************

Carbohydrates Serve as primary source of energy in the cell
Central to all metabolic processes Glucose Cytosol - anaerobic Hexokinase Pentose Phosphate Shunt Glucose-6-P Glc-1- phosphate glycolysis glycogen Pyruvate

cytosol Pyruvate mitochondria (aerobic) Aceytl CoA FATTY ACIDS Krebs
cycle Reducing equivalents AMINO ACIDS Oxidative Phosphorylation (ATP)

Glucose No mitochondria Glucose The Full Glycogen Monty Lactate
Lactate transported back to liver for glucose production “Cori Cycle”. Costs energy The Full Monty

Carbohydrate Metabolism/ Utilization- Tissue Specificity
Muscle – cardiac and skeletal Oxidize glucose/produce and store glycogen (fed) Breakdown glycogen (fasted state) Shift to other fuels in fasting state (fatty acids) Adipose and liver Glucose  acetyl CoA Glucose to glycerol for triglyceride synthesis Liver releases glucose for other tissues Nervous system Always use glucose except during extreme fasts Reproductive tract/mammary Glucose required by fetus Lactose  major milk carbohydrate Red blood cells No mitochondria Oxidize glucose to lactate Lactate returned to liver for Gluconeogenesis

Breakfast: Fate of glucose in the liver
GLUT2 Glucose Glucokinase Glucose-6-P Glycogen synthesis Pentose phosphate Glycolysis

+ Breakfast: Fate of glucose in muscle Insulin GLUT4 Glucose Glucose
Hexokinase Glucose-6-P Glycogen synthesis Glycolysis

+ + - Breakfast: Fate of glucose in adipocytes Lipoproteins Insulin
LPL + GLUT4 Glucose Fatty acids Glucose Hexokinase Glucose-6-P Insulin - Glycerol-3-P Triglycerides

Glucokinase vs. Hexokinase
Glucokinase: Km = 10 mM, not inhibited by glucose 6-phosphate. Present in liver and in pancreas b cells. Hexokinase: Km= 0.2 mM, inhibited by glucose 6-phosphate. Present in most cells.

Glucokinase vs. Hexokinase
Hexokinase has a low Km and therefore can efficiently use low levels of glucose. But is quickly saturated. Glucokinase has a high Km, so it does not become saturated till very high levels of glucose are reached Glucokinase allows liver to respond to increasing blood glucose levels At low blood glucose levels, very little is taken up by liver, so that it is spared for other tissues. Glucokinase is not inhibited by glucose 6-phosphate, allowing accumulation in liver for storage as glycogen Glucokinase is also found in b-cells of pancreas

Clinical example D.M., a 24-year-old, complaints were fatigue, weight loss, and increase in appetite, thirst, and frequency of urination. At 6 month before his visit he tired easily and tended to fall asleep in class, he had lost approximately 6.8 kg. His grandfather had had diabetes mellitus and his older sister was obese and had recently been diagnosed as having diabetes.

Diabetes mellitus and obesity
What is the basis for the symptoms of the patient? Glucose tolerance test demonstrated in ability to handle a normal glucose load Glocoseuria Familial history of diabetes Increased appetite and excessive fluid intake and fluid loss means his energy stores were being wasted and frequent urination was required for elimination of catabolic end products.

Glucose and insulin response in blood
How does the response to insulin of the obese diabetic person compare with that of the nonobese diabetic person?

Polyol pathway What role does the polyol pathway play in disturbance of carbohydrate metabolism? Glucose reduced to sorbitol and can oxidase to fructose Sorbotol stay in high concentration in lens epithelium, the Schwann cell in peripheral nerve, the papillae in kidney and the islets of Langerhans in the pancreas make cataract and neuropathy

Summary: Glucose metabolism after a carbohydrate breakfast
Net glycogen storage in liver and muscle In muscle, insulin enhances glucose uptake. In adipose tissue, insulin prevents lipolysis, enhances glucose uptake, promotes fat storage

Glycolysis Conversion of 6-carbon glucose to 3-carbon pyruvate. Pyruvate is converted to lactate when oxygen is low. Glycolysis is anaerobic; aerobic metabolism of pyruvate takes place in the TCA cycle. Requires some investment of energy to produce ATP. ATP is produced to a much lesser extent than in oxidative phosphorylation. ATP produced can be important, especially in muscle. Occurs in cytosol, so resulting compounds must be transported to mitochondria for subsequent metabolism by TCA cycle.

Glycolysis requires investment of energy
Phosphorylation traps glucose in the cell Allosteric enzyme, plays a critical role in regulation The two phosphorylation steps require 2 ATP.

Glycolysis, continued Not directly in the glycolysis pathway; must be salvaged by isomerization to glyceraldehyde 3-P Two 3-carbon fragments are produced from one 6-carbon sugar. Thus far, 2 ATPs consumed, 0 ATPs produced.

Glycolysis, continued: generation of ATP
substrate level phosphorylation rearrangement dehydration Oxidation of two 3-carbon fragments yields 4 ATP (net = 2ATP)

The figure is found at http://www. nd. edu/~aseriann/dpg
The figure is found at (March 2007)

Control points in glycolysis
hexokinase Glucose-6-P - *

Regulation of glycolysis
Glycolytic flux is controlled by need for ATP and/or for intermediates formed by the pathway (e.g., for fatty acid synthesis). Control occurs at sites of irreversible reactions Hexokinase or glucokinase Phosphofructokinase- major control point; first enzyme “unique” to glycolysis Pyruvate kinase Phosphofructokinase responds to changes in: Energy state of the cell (high ATP levels inhibit) H+ concentration (high lactate levels inhibit) Availability of alternate fuels such as fatty acids, ketone bodies (high citrate levels inhibit) Insulin/glucagon ratio in blood (high fructose 2,6-bisphosphate levels activate)

Why is phosphofructokinase, rather than hexokinase, the key control point of glycolysis?
Glucose-6-phosphate has many functions. It is the start of glycolysis glycogen synthesis pentose phosphate pathway. Phosphofructokinase (PFK-1) catalyzes the first unique and irreversible reaction in glycolysis.

The switch: Allosteric inhibition
Allosteric means “other site” Active site E Allosteric site © 2008 Paul Billiet ODWS

Switching off These enzymes have two receptor sites
One site fits the substrate like other enzymes The other site fits an inhibitor molecule Inhibitor molecule Substrate cannot fit into the active site Inhibitor fits into allosteric site © 2008 Paul Billiet ODWS

The allosteric site the enzyme “on-off” switch
Active site E Allosteric site empty E Conformational change Substrate fits into the active site Inhibitor molecule is present Substrate cannot fit into the active site The inhibitor molecule is absent Inhibitor fits into allosteric site © 2008 Paul Billiet ODWS

Phosphofructokinase This enzyme an active site for fructose-6-phosphate molecules to bind with another phosphate group It has an allosteric site for ATP molecules, the inhibitor When the cell consumes a lot of ATP the level of ATP in the cell falls No ATP binds to the allosteric site of phosphofructokinase The enzyme’s conformation (shape) changes and the active site accepts substrate molecules © 2008 Paul Billiet ODWS

Maintaining redox balance
Since the cytosol has a limited amount of NAD+, newly formed NADH must be oxidized to regenerate NAD+ for glycolysis to continue. pyruvate Aerobic - NADH is oxidized in mitochondria through further metabolism of acetyl CoA in the TCA cycle Anaerobic - NADH is oxidized by conversion of pyruvate to lactate, catalyzed by lactate dehydrogenase Anaerobic Aerobic lactate acetylCoA

Fates of Pyruvate under Anaerobic Conditions: Fermentation

Formation of acetyl CoA
Under aerobic conditions, pyruvate is not reduced to lactate, but decarboxylated to acetate, which links to Coenzyme A. Catalyzed by pyruvate dehydrogenase (PDH) multi-enzyme complex consisting of 3 catalytic subunits and several cofactors. PDH is directly inhibited by NADH, acetyl CoA, and ATP. PDH exists in phosphorylated (inactive) and dephosphorylated (active) states. Insulin stimulates dephosphorylation. PDH PDH-PO4 (active) (inactive) Protein kinase Phosphatase Insulin +

Figure 17–5. Oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex. Lipoic acid is joined by an amide link to a lysine residue of the transacetylase component of the enzyme complex. It forms a long flexible arm, allowing the lipoic acid prosthetic group to rotate sequentially between the active sites of each of the enzymes of the complex. (NAD+, nicotinamide adenine dinucleotide; FAD, flavin adenine dinucleotide; TDP, thiamin diphosphate.)

Clinical example A full-term male infant failed to gain weight, had episodes of vomiting and showed metabolic acidosis in the neonatal period. A physical examination at 8 mo showed failure to thrive, hypotonia, small muscle mass, severe head leg, and a persistent acidosis, pH 7 to 7.2. Blood lactate (9mmol/L), pyruvate (2.4 mmol/L), and alanin(1.36 mmol/L) were greatly elevated.

Genetic defect in pyruvate dehydrogenase complex
Why were the plasma concentration of pyruvate, lactate, and alanine abnormally high? Enzyme activity of the PDH complex, α- Ketodehydrogenase complex, and dihydrolipoyl dehydrogenase from sonicated fibroblasts grown in culture were are low when compared with enzymes from normal fibroblasts. Explain how these finding happening?

Overview of citric acid cycle
(TCA or Krebs cycle) Oxidation of two-carbon units, producing 2 CO2, 1 GTP, and high-energy electrons in the form of NADH and FADH2. citrate Mitochondrial matrix

Citric acid cycle For reference only NAD NADH CO2 NADH NAD NAD
Pyruvate dehydrogenase Citrate synthase Aconitase Pyruvate Citrate NAD H2O NADH CO2 Aconitase cis-Aconitate Oxaloacetate Malate dehydrogenase H2O NADH NAD Isocitrate Citric acid cycle Isocitrate dehydrogenase Malate For reference only Fumarase H2O NAD NADH CO2 Oxalosuccinate FADH2 NADH CO2 Fumarate FAD Isocitrate dehydrogenase NAD Succinate dehydrogenase GDP GTP -Ketoglutarate Succinate Succinyl-CoA synthetase -Ketoglutarate dehydrogenase Succinyl-CoA

Control points in the citric acid cycle
Rate is adjusted to meet the cell’s need for ATP. Three allosteric enzyme control points: PDH - inhibited by NADH, acetyl CoA, and ATP. Isocitrate dehydrogenase - stimulated by ADP; inhibited by ATP and NADH a-ketoglutarate dehydrogenase—inhibited by NADH, succinyl CoA, high energy charge.

Oxidative Phosphorylation
Citric Acid Cycle and Oxidative Phosphorylation Anaerobic Aerobic Glycolysis harvests only a fraction of the ATP available from glucose. Complete oxidation to CO2 takes place in the citric acid cycle. In oxidative phosphorylation, electrons removed in oxidation reduce O2 to generate a proton gradient and synthesize large amounts of ATP.

Glucose metabolism: Lunch
2 4 6 8 Insulin 100 200 300 400 500 Glucose Plasma glucose (mmol/l) Plasma insulin (pmol/l) Lunch 8 am 6 pm midnight 8 am Time of day Glycogen synthesis in liver and muscle continue with little lag; storage in adipose tissue will continue. Changes are rapid due to previous induction of glucose- and insulin-regulated genes.

Glucose metabolism: Post-absorptive state
2 4 6 8 Insulin 100 200 300 400 500 Glucose Plasma glucose (mmol/l) Plasma insulin (pmol/l) 8 am noon 6 pm midnight 8 am Time of day Post-absorptive state

Post-absorptive state—the last meal has been absorbed from the intestinal tract, as after an overnight fast Glucose levels ~ 5 mmol/l Insulin levels ~ 60 pmol/l Glucagon levels ~ 20 pmol/l Glucose enters blood almost exclusively from the liver—about one-third from glycogen breakdown, and two-thirds from gluconeogenesis. Insulin/glucagon ratio

Post-absorptive state: glucose utilization by muscle
from Liver Glucose Glycolysis Pyruvate Alanine to Liver Lactate

Gluconeogenesis

Gluconeogenesis Mechanism to maintain adequate glucose levels in tissues, especially in brain (brain uses 120 g of the 160g of glucose needed daily). Erythrocytes also require glucose. Occurs mostly in liver (90%) and kidney (10%) Glucose is synthesized from non-carbohydrate precursors derived from muscle, adipose tissue: pyruvate and lactate (60%), amino acids (20%), glycerol (20%)

Gluconeogenesis takes energy and is regulated
hexokinase Glucose-6-P - Glucose 6-phosphatase Converts pyruvate to glucose Gluconeogenesis is NOT simply the reverse of glycolysis; it utilizes unique enzymes (pyruvate carboxylase, PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase) for irreversible reactions. 6 ATP equivalents are consumed in synthesizing 1 glucose from pyruvate in this pathway

Irreversible steps in gluconeogenesis
First step by a gluconeogenic-specific enzyme occurs in mitochondria pyruvate oxaloacetate Pyruvate carboxylase Oxaloacetate is reduced to malate so that it can be transported to the cytosol. In the cytosol, oxaloacetate is then decarboxylated/phosphorylated by PEPCK (phosphoenolpyruvate carboxykinase), a second enzyme unique to gluconeogenesis. The resulting phosphoenol pyruvate is metabolized by glycolysis enzymes in reverse, until the next irreversible step

Irreversible steps in gluconeogenesis (continued)
Fructose 1,6-bisphosphate + H2O Fructose 1,6- bisphosphatase fructose-6-phosphate + Pi In liver, glucose-6-phosphate can be dephosphorylated to glucose, which is released and transported to other tissues. This reaction occurs in the lumen of the endoplasmic reticulum. Requires 5 proteins! 1) G-6-P transporter 2) Ca-binding stabilizing protein (SP) 4) Glucose transporter 5) Pi transporter 3) G-6-Pase

Post-absorptive state: glucose production by liver
Peripheral tissues Lactate Alanine Glycerol Glycogenolysis Gluconeogenesis Glucose Glucose

Substrate cycles between tissues provide substrates for gluconeogenesis in liver. This requires incomplete oxidation of glucose in tissues such as muscle and blood cells. Substrates for gluconeogenesis: Lactate—60% (muscle, blood cells) Alanine—20% (muscle) Glycerol—20% (adipose tissue) Cori Cycle—Lactate released as end product of glycolysis in peripheral tissue is returned to the liver for gluconeogenesis. Alanine Cycle—Amino groups derived from proteolysis followed by TCA cycle are transferred to pyruvate, giving rise to alanine. Alanine is used for gluconeogenesis in liver.

Cooperation between peripheral tissues and liver to maintain blood glucose level (alanine and Cori cycles)

How is metabolism regulated?
(anabolic) (catabolic) Movement Active transport Signal amplification Biosynthesis Oxidation of fuel molecules High energy charge inhibits catabolic pathways and stimulate anabolic pathways

Fast mechanisms, for immediate changes Substrate concentration Allosteric regulation (feedback, feed forward) Phosphorylation-dephosphorylation Signals emanating from hormone action Slow mechanisms, for long-term changes Genetic regulation Response to diet and other environmental variables

long term effects Rapid effect Rapid effects

Phosphofructokinase (PFK-1) as a regulator of glycolysis
fructose-6-phosphate fructose-1,6-bisphosphate PFK-1 PFK-1 is allosterically inhibited by: High ATP: lowers affinity for fructose-6-phosphate by binding to a regulatory site distinct from catalytic site. High H+: reduces activity to prevent excessive lactic acid formation and drop in blood pH (acidosis). Citrate: signals ample biosynthetic precursors and availability of fatty acids or ketone bodies for oxidation.

Phosphofructokinase (PFK-1) as a regulator of glycolysis
PFK-1 is also activated by: Fructose-2,6-bisphosphate (F-2,6-P2) F-6-P F-1,6-P2 F-2,6-P2 glycolysis + PFK-2 PFK-1 F-2,6-P2 Activates PFK-1 by increasing its affinity for fructose-6-phosphate and diminishing the inhibitory effect of ATP.

Phosphofructokinase-2 (PFK-2) is also a phosphatase (bifunctional enzyme)
Phosphorylation of bifunctional enzyme decreases kinase activity activates phosphatase fructose-6-phosphate fructose-2,6-bisphosphate phosphatase kinase ATP ADP Pi

Hormonal control of F-2,6-P2 levels and glycolysis
Hormonal regulation of bifunctional enzyme Glucagon increases cAMP levels in liver, activates cAMP-dependent protein kinase, which phosphorylates PFK2, decreases F-2,6-P inhibits glycolysis Insulin decreases cAMP, increases F-2,6-P stimulates glycolysis. Phosphorylation of PFK2 activates its phosphatase activity

Daily energy intake vs. output
Snack 50 100 150 Breakfast Lunch Evening meal Energy intake (kJ/min) We need a mechanism to store food energy and release it when it is needed. Periods of exercise 10 20 30 Energy output (kJ/min) sleep Time of Day

Energy storage forms Fatty acid Glucose Triacylglycerol (fat) Glycogen

Energy Reserves of Humans
kcal/g 4 9 ~24 hr supply for body (brain) Not available for export as glucose

Glucose storage as glycogen
Schematic representation of glycogen molecule Glycogen granules in liver Protein Glycogen is a multi-branched glucose polymer with up to 60,000 glucose residues. Glucose residues linked a 1,4 in linear chains and a 1,6 at branch points. Molecular weight in the millions. Stored in liver and muscle as cytoplasmic granules—amount varies depending on time and size of recent meals Valuable as a storage form because it is a readily mobilized form of glucose Glycogen breakdown (glycogenolysis) and glycogen synthesis occur by separate pathways.

Glycogenolysis Glycogen Glucose 1-phosphate Glucose 6-phosphate
Glycogen phosphorylase—sequentially removes glucose from ends of glycogen chains by phosphorolytic cleavage. This produces glucose that is already phosphorylated. Additional enzymes are required for ‘debranching’. Glycogen Glycogen phosphorylase, phosphate Glucose 1-phosphate Phosphoglucomutase— catalyzes a shift in the phosphate group from C-1 to C-6. Reaction is reversible. Phosphoglucomutase Glucose 6-phosphate In liver, glucose 6-phosphate can be cleaved to glucose by glucose 6-phosphatase, to be released to blood and transported to other organs. Other pathways are available to all organs. Pentose phosphate Glucose Glycolysis

Glucose-6- phosphatase
Glycogen degradation: phosphorylase a-1,4 linked glucose residues in linear chains a-1,6 linked glucose residues at branch points Glycogen Phosphorylase, phosphate Glycogen Phosphogluco- mutase Glucose-6- phosphatase Glucose-1- phosphate Glucose-6- phosphate Glucose

Glycogen degradation: debranching enzyme
1 enzyme with 2 catalytic sites Glycogen α-1,6- glucosidase Transferase Debranching enzyme Glycogen α-1,6- glucosidase Transferase Debranching enzyme Glycogen

UDP-glucose pyrophosphorylase
Glycogen synthesis: glycogen synthase UTP UDP-glucose pyrophosphorylase Phosphogluco- mutase Glucose-1- phosphate Glucose-6- phosphate UDP-Glucose H Glycogen synthase Glycogenin UDP Glycogen

Glycogen synthesis: branching enzyme

Reciprocal regulation of glycogen synthesis and breakdown
Activity of glycogen synthase and glycogen phosphorylase are regulated by phosphorylation/dephosphorylation. Phosphorylation activates glycogen phosphorylase, inactivates glycogen synthase. Catalyzed by special kinases. Dephosphorylation is catalyzed by protein phosphatase 1. Glycogen UDP-Glucose Synthase-Pb Phosphorylaseb Glucose-1-phosphate Phosphorylase-Pa synthasea Active forms of enzymes = ‘a’ Inactive forms of enzymes = ‘b’

Reciprocal regulation of glycogen synthesis and breakdown
Mechanisms regulating glycogen synthesis and degradation are complex Regulation by phosphorylation states Cascade of reactions, starting with hormonal stimulation Glucagon/epinephrine activate cAMP-activated protein kinase A, which activates “phosphorylase kinase”, which then phosphorylates glycogen phosphorylase Effect of insulin opposite to that of glucagon: stimulates phosphatases Regulation by allosteric effectors Glucose 6-phoshate activates glycogen synthase, inhibits glycogen phosphorylase ATP inhibits phosphorylase Glucose inhibits phosphorylase (in liver) Ca++ and AMP activate phosphorylase (in muscle)

Glucose regulates liver glycogen metabolism
In liver, phosphorylase a is inhibited allosterically by glucose. Glucose activates glycogen synthase (indirectly)

Hormonal stimulation of glycogenolysis
Glucagon Epinephrine + + ATP ATP cAMP Glycogen - + UDP-glucose Glucose 1-P - Pyruvate Glucose 6-P Pyruvate liver muscle Fat Glucose

Pompe disease (glycogenosis type II) is a lysosomal storage disease
muscle weakness; enlarged heart Lysosomal accumulation of glycogen (not epinephrine responsive because sequestered by lysosomal membrane)

How would you treat it? How would you treat it?
Pompe disease (type II glycogen storage disease) is caused by deficiency of lysosomal a-glucosidase, which normally degrades glycogen in lysosomes. Von Gierke disease (type I glycogen storage disease) is caused by inability to generate glucose from glucose 6-phosphate. That enzyme is key to keeping blood glucose level up during the overnight fast. How would you treat it?

Glycogen storage diseases
For reference only

Alternative fates of glucose in the cell
Glucose 6-phosphate 6-phosphogluconate Glycogen pyruvate Ribose 5-phosphate

Pentose phosphate pathway
AKA “pentose shunt” or “hexose monophosphate” shunt Major Functions: Synthesis of pentose sugars for DNA, RNA, ATP, NADH, FAD Generate NADPH from NADP+ for biosynthetic reactions Minor Functions: Interconversion of 3,4,5,6, and 7 carbon sugars Generate glycolytic intermediates Rate is controlled by levels of NADP+ Glucose-6-P dehydrogenase

Clinical example Fauvism

Glucose 6-phosphate + NADP+ 6-phosphoglucono-d-lactone + NADPH + H+
Dehydrogenase Glucose 6-phosphate dehydrogenase First step in pentose phosphate pathway: Required for generation of NADPH in erythrocytes; deficiency leads to hemolytic anemia induced by drugs or infection. Cells cannot maintain reduced glutathione. G6PD deficiency affects over 200 million people. High incidence in some parts of the world suggests that it confers a selective advantage against the malaria parasite. Heinz bodies in red cells represent denatured proteins (including hemoglobin) lactonase H20 6-phosphogluconate

Roles of NADPH Biosynthesis Fatty acids Cholesterol Neurotransmitters
Nucleotides Detoxification Reduction of oxidized GSH in erythrocytes: Keeps hemoglobin iron in a ferrous state Stabilizes erythrocyte membrane g-Glu—Cys—Gly S 2 g-Glu—Cys—Gly SH + NADPH + H+ + NADP+ Oxidized Glutathione (GSH) Reduced glutathione (disulfide form) (sulfhydryl form)

Pentose phosphate pathway
AKA “pentose shunt” or “hexose monophosphate” shunt Major Functions: Synthesis of pentose sugars for DNA, RNA, ATP, NADH, FAD Generate NADPH from NADP+ for biosynthetic reactions Minor Functions: Interconversion of 3,4,5,6, and 7 carbon sugars Generate glycolytic intermediates Rate is controlled by levels of NADP+ Glucose-6-P dehydrogenase

Clinical example A child had nausea, vomiting, and symptoms of hypoglycemia: sweating, dizziness, and trembling. It was reported that these attacks occurred shortly after eating fruit or cane sugar. This child was below normal weight, had cirrhosis of liver, a normal glucose tolerance test, and reducing substances in the urine that did not glucose.

Clinical example A boy with normal weight was born. From the third day of life the child developed an increasing degree of jaundice and at the same time become indolent and difficult to feed. Between the 7th and 9th days, exchange blood transfusion was performed three times, but the serum bilirubin concentration still remained high. A positive test for reducing sugars was in urine. Hereditary galactosemia was then suspected and special tests was performed.

Carbohydrate metabolism

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