III - Carbohydrates Flashcards
Most abundant organic molecules in nature
Carbohydrates
Empiric Formula: (CH2O)n - hydrates of carbon
Carbohydrates
Functions of Carbohydrates
energy source, storage form of energy, part of cell membranes, structural components
Polymers of repeating sugar units
Carbohydrates
One sugar unit
monosaccharide
Two sugar units
disaccharide
3-10 sugar units
oligosaccharide
> 10 sugar units
polysaccharide
How many sugar units do monosaccharides have?
One
How many sugar units do disaccharides have?
Two
How many sugar units do oligosaccharides have?
3-10
How many sugar units do polysaccharides have?
> 10
The simplest and most basic form of carbohydrate hence cannot be hydrolyzed further
monosaccharide
From fruit juices, hydrolysis of cane sugar, maltose and lactose
Glucose
The “sugar of the body”, carried by the blood, principal sugar used by the tissues
Glucose
Present in urine in DM owing to its high levels in the blood
Glucose
Found in fruit juices, honey, hydrolysis of cane sugar and inulin (from the Jerusalem artichoke)
Fructose
Can be changed to glucose in the liver and so used in the body
Fructose
Hereditary _____ intolerance leads to _____ accumulation and hypoglycemia
Fructose
From the hydrolysis of lactose
Galactose
Can be changed to glucose in the liver and metabolized, synthesized in the mammary gland to make the lactose of milk, a constituent of glycolipids and glycoproteins
Galactose
Failure to metabolize _____ leads to cataracts
Galactose
from the hydrolysis of plant mannans and gums
Mannose
A constituent of many glycoproteins
Mannose
Monosaccharide found in nucleic acids
Ribose
Monosaccharides found in glycoproteins
Xylose, Arabinose, Mannose
Monosaccharide found in proteoglycans
Neuraminic Acid
Monosaccharide found in cardiac tissue
Lyxose
Ribose is found in
nucleic acids
Xylose is found in
glycoproteins
Arabinose is found in
glycoproteins
Mannose is found in
glycoproteins
Neuraminic Acid is found in
proteoglycans
Lyxose is found in
cardiac tissue
Condensation product of two monosaccharide units, linked by glycosidic bonds
disaccharide
Glucose + Glucose
Maltose - α(1→4)
Glucose + Galactose
Lactose - β(1→4)
Glucose + Fructose
Sucrose - α1→β2
From germinating cereals, malt, digestion by amylase or hydrolysis of starch
Maltose
From milk, found in urine during pregnancy
Lactose
From sorghum, pineapples, carrots, cane and beet sugar
Sucrose
From fungi and yeasts, the major source of insect hemolymph
Trehalose
Condensation product of 3-10 monosaccharides, most are not digested by human enzymes, maltotriose
Oligosaccharide
Condensation product of >10 monosaccharides, may be linear or branched, easily digested
Polysaccharide
Homopolymer of glucose forming an α-glucosidic chain called glucosan or glucan
Starch
Most important dietary source of carbohydrate in cereals, potatoes, legumes and other vegetables
Starch
Storage polysaccharide in animals (“animal starch”)
Glycogen
More highly branched structure than amylopectin with chains of 12-14 α-D-glucopyranose residues with α(1→4) glycosidic linkage with branching via α(1→6) glycosidic bonds
Glycogen
Polysaccharide of fructose used to determine the GFR
Inulin
Chief constituent of plant cell walls, fiber, cannot be digested
Cellulose
Insoluble and consists of β-D-glucopyranose units linked by β(1→4) bonds to form long, straight chains strengthened by cross-linking H-bonds
Cellulose
Also known as mucopolysaccharides
Glycosaminoglycans
Complex carbohydrates containing amino sugars and uronic acids
Glycosaminoglycans
May be attached to a protein molecule to form a proteoglycan
Glycosaminoglycans
Also known as mucoproteins, found in cell membranes
Glycoproteins
Proteins containing branched or unbranched oligosaccharide chains
Glycoproteins
Compounds that have the same chemical formula but different structures
Isomers
Compounds that differ in configuration around only one specific carbon atom with the exception of the carbonyl atom
Epimers
Pairs of structures that are mirror images of each other
Enantiomers/Stereoisomers/Optical Isomers - Dextro- (R), Levo- (L)
More common configuration of sugars in the body (D vs. L)
Dextro- (R)
Compounds that differ in configuration (linear/ring)
Anomers
More common configuration of sugars in the body (linear vs. cyclic)
Cyclic
Linear form of sugars
Fischer Projection
Cyclic form of sugars
Haworth Projection
5C Ring
Furan
6C Ring
Pyran
α and β forms of sugar spontaneously interconvert through a process called
Mutarotation
Physical digestion in the mouth
Mastication
Amylase can only digest _____ glycosidic bonds
α(1→4) - glycogen
Facilitates diffusion for all sugars, found in the basement membrane
GLUT-2 Transporter
Facilitates diffusion for all sugars, found in the lumen of the SI
GLUT-5 Transporter
A secondary active transporter for glucose and galactose (needs Na-K-ATPase), Na/hexose symporter, for glucose and galactose
SGLT-1 Trasporter
Tells how fast a carbohydrate is absorbed compared to glucose and galactose
Glycemic Index
Fast Absorption: GI _ 1
GI > 1
Slow Absorption: GI _ 1
GI < 1
Food with ___ GI is beneficial for DM.
low GI
Disaccharidase deficiency found in Asians
Lactose Intolerance / Lactase Deficiency
Disaccharidase deficiency found in Greenland Eskimos
Isomaltase-Sucrase Deficiency
Acquired enzyme deficiency occurs during _____ where enzymes are removed in stool.
severe diarrhea
Sum of all the chemical reactions in a cell, tissue or the whole body
Metabolism
Synthesis of compounds from smaller raw materials
Anabolic Metabolism
An endergonic and divergent process
Anabolic Metabolism
Breakdown of larger molecules
Catabolic Metabolism
An exergonic and convergent process, usually oxidative
Catabolic Metabolism
Produces reducing equivalents and ATP mainly via the ETC
Catabolic Metabolism
Crossroads of metabolism, links anabolic and catabolic pathways
Amphibolic Metabolism
Regulators of Metabolism: signals from within the cell
substrate avaiability, product inhibition, allosteric activators/inhibitors
Regulators of Metabolism: communication between cells
gap junctions (direct contact), neurotransmitters (synaptic signaling), hormones (endocrine signaling)
Regulators of Metabolism: second messenger systems
calcium/inositol triphosphate (ITP), adenylyl cyclase system (cAMP), guanylate cyclase system (cGMP)
Inositol Triphosphate System: G Protein
Gq
Inositol Triphosphate System: Substrate
Phosphatidylinositol - found in the cell membrane, acted on by phospholipase C
Inositol Triphosphate System: 2nd Messengers
Diacyl glycerol (DAG) - activates protein kinase C, Inositol Triphosphate (ITP) - release intracellular Ca
Membrane-bound enzyme that converts ATP to cyclic AMP (cAMP) in response to hormones
Adenylyl cyclase
Hydrolyzes cAMP to 5’-AMP
cAMP phosphodiesterase
Adenylyl Cyclase System: G Protein
Gs - stimulates, increase cAMP, Gi - inhibits, decrease cAMP
Adenylyl Cyclase System: Substrate
ATP
Adenylyl Cyclase System: 2nd Messengers
cAMP - activates protein kinase A
GLUT-1 is found in
erythrocytes, brain, kidneys, colon, placenta
GLUT-2 is found in
liver, pancreatic β-cells, small intestines, kidneys
GLUT-3 is found in
brain, kidneys, placenta
GLUT-4 is found in
heart and skeletal muscle, adipose
GLUT-5 is found in
small intestines
GLUT Transporter in erythrocytes, brain, kidneys, colon, placenta
GLUT-1
GLUT Transporter in liver, pancreatic β-cells, small intestines, kidneys
GLUT-2
GLUT Transporter in brain, kidneys, placenta
GLUT-3
GLUT Transporter in heart and skeletal muscle, adipose
GLUT-4
GLUT Transporter in small intestines
GLUT-5
Function of GLUT-1
uptake of glucose
Function of GLUT-2
rapid uptake and release of glucose
Function of GLUT-3
uptake of glucose
Function of GLUT-4
insulin-stimulated uptake of glucose
Function of GLUT-5
absorption of glucose
Major pathway for glucose metabolism that converts glucose into 3C compounds to provide energy
Glycolysis
Glycolysis: Location
Cytoplasm, all cells
Glycolysis: Substrate
Glucose
Glycolysis: End-Product
Pyruvate or Lactate - depends on the availability of oxygen or mitochondria
Glycolysis: Rate-Limiting Step
fructose 6-phosphate → fructose 1,6-bisphosphate
Glycolysis: Rate-Limiting Enzyme
Phosphofructokinase 1
Occurs in cells with mitochondria in the presence of oxygen to produce Pyruvate
Aerobic Glycolysis
Occurs in cells without mitochondria without oxygen to produce Lactate
Anaerobic Glycolysis
3 Irreversible Steps in Glycolysis
Step 1: phosphorylation of glucose, Step 3: phosphorylation of fructose 6-phosphate, Step 10: formation of pyruvate
Glycolysis: Step 1
glucose → glucose 6-P
Phosphorylates glucose in the first step of glycolysis
Hexokinase or Glucokinase
Phosphorylates glucose in most tissues with low Km (high affinity) and low Vmax, inhibited by glucose 6-P
Hexokinase
Phosphorylates glucose in liver parenchyma and pancreatic islets with high Km (low affinity) and high Vmax, inhibited by fructose 6-P, induced by insulin
Glucokinase
Glucose phosphorylator that is saturated in the liver and acts in a constant rate to provide glucose 6-P to meet the cell’s need
Hexokinase
Glucose phosphorylator that removes glucose from the blood following a meal providing glucose 6-P in excess requirements for glycolysis which is used for glycogenesis and lipogenesis
Glucokinase
Glycolysis: Step 3
fructose 6-phosphate → fructose 1,6-bisphosphate
Phosphofructokinase 1 converts fructose 6-P to _____
fructose 1,6-BP
Converts fructose 6-P to fructose 1,6-BP
PFK1 - Phosphofructokinase 1
Phosphofructokinase 1 activators
fructose 2,6-BP, AMP
Phosphofructokinase 1 inhibitors
ATP, Citrate
Phosphofructokinase 2 converts fructose 6-P to _____
fructose 2,6-BP
Converts fructose 6-P to fructose 2,6-BP
Phosphofructokinase 2
Phosphofructokinase 2 activators
well-fed state - high insulin, low glucagon
Phosphofructokinase 2 inhibitors
fasting state - low insulin, high glucagon
Glycolysis: Step 10
phoshoenolpyruvate (PEP) → pyruvate
Forms pyruvate from PEP in glycolysis
Pyruvate kinase
Pyruvate kinase activator
fructose 1,6-BP - feedforward mechanism
Pyruvate kinase inhibitors
glucagon + cAMP = phosphorylation
ATP Consumption in Glycolysis
glucose → glucose 6-P (hoxokinase or glucokinase), fructose 6-phosphate → fructose 1,6-bisphosphate (phosphofructokinase 1)
ATP Production in Glycolysis
1,3-biphosphoglycerate → 3-phosphoglycerate (phosphoglycerate kinase), phosphoenolpyruvate → pyruvate (pyruvate kinase)
NADH Production in Glycolysis
glyceraldehyde 3-phosphate → 1,3-bisphosphoglycerate (glyceraldehyde 3-phosphate dehydrogenase)
Aerobic Glycolysis: Pyruvate
enters the Citric Acid Cycle
Aerobic Glycolysis: ATP Yield
6 or 8
Anaerobic Glycolysis: Pyruvate
reduced to lactate by NADH
Anaerobic Glycolysis: ATP Yield
2
NADH Shuttle found in liver, kidneys and brain
Malate-Aspartate Shuttle
Malate-Aspartate Shuttle is found in
liver, kidneys and brain
Malate-Aspartate Shuttle yields _ ATP
3 ATP
NADH Shuttle found in skeletal muscle and brain
Glycerol Phosphate Shuttle
Glycerol Phosphate Shuttle is found in
skeletal muscle and brain
Glycerol Phosphate Shuttle yields _ ATP
2 ATP
Strictly glycolytic organs
RBCs, testes, lens, cornea, kidney medulla, WBCs
Used to reduce pyruvate to lactate
NADH
Conversion to lactate is the major fate of pyruvate in
RBCs, testes, lens, cornea, kidney medulla, WBCs
Found in RBCs where phosphoglycerate kinase is bypassed
2,3-bisphosphoglycerate (2,3-BPG)
Catalyzes 1,3-BPG → 2,3-BPG
bisphosphoglycerate mutase
Catalyzed by bisphosphoglycerate mutase
1,3-BPG → 2,3-BPG
Inhibits pyruvate dehydrogenase by binding to lipoic acid, competes with inorganic phosphate as a substrate for glyceraldehyde 3-P dehydrogenase
Arsenic (Pentavalent)
Most common enzyme deficiency in glycolysis, manifests as intravascular hemolytic anemia
Pyruvate Kinase Deficiency
Glycolytic enzyme deficiency which manifests as low exercise capacity particularly on high carbohydrate diets
Muscle Phosphofructokinase Deficiency
Fate of Pyruvate: Citric Acid Cycle
Acetyl CoA (pyruvate dehydrogenase)
Fate of Pyruvate: Anaerobic Glycolysis
Lactate (lactate dehydrogenase)
Fate of Pyruvate: Fermentation
Ethanol (pyruvate decarboxylase)
Fate of Pyruvate: Gluconeogenesis
Oxaloacetate (pyruvate carboxylase)
Pyruvate dehydrogenase coenzymes
Lipoic Acid, NAD, FAD, Thiamine pyrophosphate (B1 derivative), Coenzyme A
Pyruvate dehydrogenase substrate
Pyruvate
Pyruvate dehydrogenase products
Acetyl CoA, NADH, CO2
Pyruvate dehydrogenase activators
NAD, CoA, Pyruvate
Pyruvate dehydrogenase inhibitors
NADH, Acetyl CoA, ATP
Most common cause of congenital lactic acidosis, x-linked dominant, dec. acetyl CoA deprives brain causing psychomotor retardation and death, treated with ketogenic diet
Pyruvate Dehydrogenase Deficiency
An acquired pyruvte dehydrogenase deficiency aggravated by thiamine deficiency leading to fatal pyruvic and lactic acidosis
Chronic Alcoholism
Final common pathway for the aerobic oxidation of all nutrients
Tricarboxylic Acid Pathway/Krebs Cycle/Citric Acid Cycle
Provides majority of ATP for energy, gluconeogenesis from AA skeletons, building blocks for AA and heme (succinyl CoA)
TCA Pathway
TCA Pathway: Functions
provides majority of ATP for energy, gluconeogenesis from AA skeletons, building blocks for AA and heme (succinyl CoA)
TCA Pathway: Location
Mitochondrial matrix (except succinyl dehydrogenase - inner mitochondrial membrane), all cells with mitochondria
TCA Pathway: Substrate
Acetyl CoA
TCA Pathway: Products
3 CO2, GTP, 4 NADH, FADH
TCA Pathway: Rate-Limiting Step
isocitrate → α-ketoglutarate
TCA Pathway: Rate-Limiting Enzyme
isocitrate dehydrogenase
TCA Pathway: ATP Yield from Acetyl CoA
12
TCA Pathway: ATP Yield from Pyruvate
15
TCA Pathway Sequence
Citrate 6C, Isocitrate 6C, α-Ketoglutarate 5C, Succinyl CoA 4C, Succinate 4C, Fumarate 4C, Malate 4C, Oxaloacetate 4C
Acetyl CoA + Oxaloacetate → Citrate
Citrate Synthase
Catalyzed by citrate synthase
Acetyl CoA + Oxaloacetate → Citrate
Citrate → Isocitrate (isomerization)
Aconitase
Catalyzed by aconitase
Citrate → Isocitrate (isomerization)
Inhibits aconitase
Fluooroacetate (rat poison)
Isocitrate → α-Ketoglutarate
Isocitrate dehydrogenase (rate-limiting enzyme)
Catalyzed by isocitrate dehydrogenase
Isocitrate → α-Ketoglutarate (rate-limiting step)
Products from Isocitrate → α-Ketoglutarate (isocitrate dehydrogenase)
CO2, NADH
α-Ketoglutarate → Succinyl CoA
α-Ketoglutarate dehydrogenase
Catalyzed by α-ketoglutarate dehydrogenase
α-Ketoglutarate → Succinyl CoA
Coenzymes for α-ketoglutarate dehydrogenase
Thiamine Pyrophosphate (B1 derivative), Lipoic Acid, FAD
Products from α-Ketoglutarate → Succinyl CoA (α-ketoglutarate dehydrogenase)
CO2, NADH
Inhibits α-ketoglutarate dehydrogenase
Arsenite
Succinyl CoA → Succinate
Succinate thiokinase
Catalyzed by succinate thiokinase
Succinyl CoA → Succinate
Product from Succinyl CoA → Succinate (succinate thiokinase)
GTP (ATP equivalent)
Succinate → Fumarate
Succinate dehydrogenase
Catalyzed by succinate dehydrogenase
Succinate → Fumarate
Product from Succinate → Fumarate (succinate dehydrogenase)
FADH2
Fumarate → Malate
Fumarase (fumarate hydratase)
Catalyzed by fumarase (fumarate hydratase)
Fumarate → Malate
Malate → Oxaloacetate
Malate dehydrogenase
Catalyzed by malate dehydrogenase
Malate → Oxaloacetate
Product of Malate → Oxaloacetate (malate dehydrogenase)
NADH
TCA Intermediates: _____ delivers acetyl CoA to the cytoplasm for fatty acid synthesis via _____ shuttle.
Citrate
TCA Intermediates: Used for heme synthesis and activation of ketone bodies in extrahepatic tissues
Succinyl CoA
TCA Intermediates: May be used for gluconeogenesis
Malate
Production of new glucose
Gluconeogenesis
Gluconeogenesis can produce glucose from these intermediates
intermediates of glycolysis and the TCA cycle, glycerol from TGs, lactate through the Cori Cycle, carbon skeletons (α-ketoacids) of glucogenic AAs
Gluconeogenesis: Location
liver (90%), kidney (10%, 40% during fasting), both in the mitochondria and cytoplasm
Gluconeogenesis: Substrate
Pyruvate
Gluconeogenesis: Product
Glucose
Gluconeogenesis: Rate-Limiting Step
fructose 1,6-bisphosphate → fructose 6-phosphate
Gluconeogenesis: Rate-Limiting Enzyme
Fructose 1,6-bisphosphatase
Lactate generated during anaerobic metabolism is brought to the liver the be converted to glucose via hepatic gluconeogenesis.
Cori Cycle
The Cori Cycle uses _ ATP to produce glucose.
4 ATP
Important Steps in Gluconeogenesis
Step 10: pyruvate → OAA → PEP, Step 3: fructose 1,6-BP → fructose 6-P, Step 1: glucose 6-P → glucose
Gluconeogenesis: Step 10
pyruvate → OAA (pyruvate carboxylase), OAA → PEP (PEP carboxykinase)
Pyruvate → OAA
Pyruvate carboxylase
Pyruvate carboxylase requires
Biotin
Function of Carboxylases
Attaches a carbon atom using CO2 as a substrate
3 Carboxylase Reactions
pyruvate → OAA (pyruvate carboxylase), acetyl CoA → malonyl CoA (acetyl CoA carboxylase), propionyl CoA → succinyl CoA (propionyl CoA carboxylase)
Catalyzed by pyruvate carboxylase
Pyruvate → OAA
OAA → PEP
PEP carboxykinase
PEP carboxykinase requires
GTP
Catalyzed by PEP carboxykinase
OAA → PEP
Gluconeogenesis: Step 3
fructose 1,6-BP → fructose 6-P (fructose 1,6-bishosphatase) - rate-limiting step
Fructose 1,6-BP → Fructose 6-P
Fructose 1,6-bishosphatase
Catalyzed by fructose 1,6-bishosphatase
Fructose 1,6-BP → Fructose 6-P
Fructose 1,6-bishosphatase activator
ATP
Fructose 1,6-bishosphatase inhibitors
Fructose 2,6-BP, AMP
Performs dual functions: promote glycolysis and inhibit gluconeogenesis
Fructose 2,6-BP
Functions of Fructose 2,6-BP
activates phophofructokinase 1 (glycolysis), inhibits fructose 1,6-bishosphatase (gluconeogenesis
Gluconeogenesis: Step 1
glucose 6-P → glucose (glucose 6-phosphatase) - final step, shared with glycogen degradation
Glucose 6-P → Glucose occurs in
liver and kidneys only (muscle lacks glucose 6-phosphatase hence muscle glycogen can only be used by muscle itself)
Gluconeogenesis: Regulation
circulating levels of glucagon, availability of glucognic substrates, allosteric activation by acetyl CoA, allosteric inhibition by AMP
Gluconeogenesis: Energy Expenditure
4 ATP, 2 GTP, 2 NADH
In hyperglycemia, the glomerular filtrate may contain more glucose that can be reabsorbed. This occurs when the venous blood glucose concentration exceeds 9.5-10 mmol/L (renal threshold).
Glucosuria
In _____ high amounts of NADH is produced resulting in _____.
alcoholism, hypoglycemia
When alcohol is consumed, high amounts of cytoplasmic NADH is produced by
alcohol dehydrogenase, acetaldehyde dehydrogenase
High amounts of NADH favors
pyruvate → lactate, OAA → malate, DHAP → glycerol 3-phosphate
NADH diverts pyruvate to lactate and OAA to malate resulting in
decreased gluconeogenesis → hypoglycemia
High fetal glucose consumption results in
hypoglycemia in pregnancy
Hyperinsulinemia in pregnancy is due to _____ and causes _____.
high estrogen, fasting hypoglycemia
Insulin resistance in pregnancy is due to _____ and causes _____.
high human placental lactogen (HPL), post-prandial hyperglycemia
Causes of Hypoglycemia in the Neonate
premature and LBW babies have little adipose, enzymes for gluconeogenesis are not yet completely functional
Major storage carbohydrate in animals
Glycogen
A branched polymer f D-glucose, uses α(1→4) glycosidic bonds for elongation and α(1→6) glycosidic bonds for branching
Glycogen
Glycogen: Storage
liver - 100g, 6% of liver, muscle - 400g, < 1% of muscle
Glycogen: Primary Bond
α(1→4) - 8-10 glucosyl residues
Glycogen: Branching Bond
α(1→6)
Synthesis of new glycogen molecules from α-D-glucose
Glycogenesis
Glycogenesis: Location
Cytosol, liver and muscle
Glycogenesis: Substrates
UDP-glucose, ATP, UTP, glycogenin (core, primer protein)
Glycogenesis: Product
Glycogen
Glycogenesis: Rate-Limiting Step
addition of α(1→4) bonds
Glycogenesis: Rate-Limiting Enzyme
Glycogen synthase
Important Steps in Glycogenesis
glucose 6-P → glucose 1-P, synthesis of UDP-glucose, elongation of glycogen chain, formation of branches
Glucose 6-P → Glucose 1-P
Phosphoglucomutase
Catalyzed by phosphoglucomutase
Glucose 6-P → Glucose 1-P
Synthesis of UDP-glucose: Enzyme
UDP-glucose phosphorylase
Catalyzed by UDP-glucose phosphorylase
Synthesis of UDP-glucose
Synthesis of UDP-glucose: Substrates
glucose 1-P, UTP
Elongation of glycogen chain
Glycogen synthase forms α(1→4) glycosidic bonds between glucose residues at the non-reducing end (carbon 4) - rate-limiting step
Catalyzed by glycogen synthase
Elongation of glycogen chain - forms α(1→4) glycosidic bonds between glucose residues at the non-reducing end (carbon 4) - rate-limiting step
Formation of branches in glycogen
Branching enzyme composed of amylo-α(1→4) → α(1→6) transglucosidase forms new α(1→6) bonds by transferring 5-8 glucosyl residues
Catalyzed by branching enzyme - amylo-α(1→4) → α(1→6) transglucosidase
Formation of branches in glycogen - forms new α(1→6) bonds by transferring 5-8 glucosyl residues
1-4 residues remaining on a branch after glycogen phosphorylase has already shortened it
Limit Dextrin
Shortening of glycogen chains to produce molecules of α-D-glucose
Glycogenolysis
Glycogenolysis: Location
Cytosol, liver and muscle
Glycogenolysis: Substrate
Glycogen
Glycogenolysis: Products
free glucose, glucose 1-P, glucose 6-P in muscle
Glycogenolysis: Rate-Limiting Step
Removal of glucose - breaks α(1→4) bonds
Glycogenolysis: Rate-Limiting Enzyme
Glycogen phosphorylase
1-4 residues remaining on a branch after glycogen phosphorylase has already shortened it
Limit Dextrin
Important Steps in Glycogenolysis
removal of glucose, removal of branches, glucose 1-P → glucose 6-P, lysosomal degradation of glycogen
Removal of branches
Debranching enzyme composed of α(1→4) → α(1→4) glucantransferase (transfers limit dextrin) and amylo-α(1→6) glucosidase (removes free glucose)
Catalyzed by α(1→4) → α(1→4) glucantransferase
Transfer of limit dextrin
Catalyzed by amylo-α(1→6) glucosidase
Removal of free glucose - breaks α(1→6) bonds
Glucose 1-P → Glucose 6-P
Phosphoglucomutase: liver - further converts glucose 6-P to glucose, muscles - glucose 6-P is the final product
Catalyzed by phosphoglucomutase
Glucose 1-P → Glucose 6-P: liver - further converts glucose 6-P to glucose, muscles - glucose 6-P is the final product
Lysosomal degradation of glycogen
α(1→4) glucosidase (acid maltase)
Catalyzed by α(1→4) glucosidase (acid maltase)
Lysosomal degradation of glycogen
Glycogen synthase activators
glucose 6-P, insulin, dephosphorylation, well-fed state
Glycogen synthase inhibitors
glucagon, epinephrine, phosphorylation, fasting state
Glycogen phosphorylase activators
Ca in muscle, glucagon, epinephrine, phosphorylation, fasting state
Glycogen phosphorylase inhibitors
glucose 6-P, ATP, insulin, dephosphorylation, well-fed state
Inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in tissues, 12 types in total
Glycogen Storage Diseases
Glycogen Storage Disease Type I
Von Gierke’s
Von Gierke’s: Deficiency
glucose 6-phospatase
Von Gierke’s: Findings
glycogen in liver and renal cells
hypoglycemia
lactic acidosis/ketosis
Glycogen in liver and renal cells, hypoglycemia + lactic acidosis/ketosis
Von Gierke’s, GSD Type I
Glycogen Storage Disease Type II
Pompe’s
Pompe’s: Deficiency
acid maltase (α(1→4) glucosidase)
Pompe’s: Findings
glycogen in lysosomes
cardiomegaly
heart failure
Glycogen in lysosomes, cardiomegaly, heart failure
Pompe’s, GSD Type II
Glycogen Storage Disease Type III
Cori’s
Cori’s: Deficiency
debranching enzyme
Cori’s: Findings
glycogen in liver and renal cells
MILD hypoglycemia
lactic acidosis/ketosis
Glycogen in liver and renal cells, MILD hypoglycemia + lactic acidosis/ketosis
Cori’s, GSD Type III
Glycogen Storage Disease Type V
McArdle’s
McArdle’s: Deficiency
skeletal muscle glycogen phosphorylase
McArdle’s: Findings
glycogen in muscle
muscle cramps
myoglobinuria without lactic acidosis
Glycogen in muscle, muscle cramps + myoglobinuria without lactic acidosis
McArdle’s, GSD Type V
Important source of galactose, found in milk
Lactose
Lactose is hydrolyzed by lactase in the _____.
intestinal brush border
All disaccharidases and trisaccharidases are found in the _____.
brush border of the intestinal epithelium
Important Steps in Galactose Metabolism
phosphorylation of galactose
formation of UDP-galactose
use of galactose as a carbon source
Phosphorylation of galactose
galactose → galactose 1-P (galactokinase)
Formation of UDP-galactose (activated form of galactose)
galactose 1-P + UDP-glucose → UDP-galactose + glucose 1-P (galactose 1-P uridyltransferase)
Use of galactose as a carbon source
UDP-galactose → UDP-glucose (UDP-hexose 4-epimerase)
Galactokinase deficiency causes _____ and _____.
galactosemia, galactosuria
Causes cataracts in early childhood
Galactokinase Deficiency
Enzyme deficient in classic galactosemia
Galactose 1-P uridyltransferase
Galactitol accumulates causing cataracts within a few days after birth, hepatosplenomegaly and mental retardation
Classic Galactosemia
Vomiting and diarrhea after milk ingestion, hypoglycemia, liver disease and cirrhosis, lethargy and hypotonia, mental retardation
Classic Galactosemia
Classic galactosemia is a _____ to breastfeeding.
absolute contraindication
Important source of fructose, found in honey and fruits
Sucrose
Sucrose is hydrolyzed by sucrase in the _____.
intestinal brush border
Has the fastest metabolism and greatest yield of energy among sugars
Fructose
Important Steps in Fructose Metabolism
phosphorylation of fructose, formation of DHAP and glyceraldehyde
Phosphorylation of fructose
fructose → fructose 1-P (fructokinase or hexokinase)
Formation of DHAP and glyceraldehyde
fructose 1-P → dihydroxyacetone phosphate (DHAP) + glyceraldehyde (aldolase B)
Catalyzed by aldolase A
fructose 1,6-BP → DHAP + glycerol 3-P (glycolysis)
Catalyzed by aldolase B
fructose 1-P → DHAP + glyceraldehyde (fructose metabolism
Defective fructokinase, benugn and asymptomatic, only presents as fructosemia and fructosuria
Essential Fructosuria
Deficiency of aldolase B, autosomal recessive, fructose 1-P accumulates decreasing phosphate, glycogenolysis and gluconeogenesis
Fructose Intolerance
Severe hypoglycemia and lactic acidosis after fructose ingestion, vomiting, apathy, diarrhea, liver damage, jaundice, proximal renal tubule disorder resembling Fanconi syndrome
Fructose Intolerance
Important component of glycoproteins, very little contribution to diet
Mannose
Isomerization between mannose and fructose
mannose 6-P → fructose 6-P (phosphomannose isomerase)
Sorbitol metabolism in lens, retina, Schwann cells, liver, kidney, placenta, RBCs, ovaries, seminal vesicles
glucose → sorbitol (aldose reductase)
Sorbitol metabolism only found in the seminal vesicles
sorbitol → fructose (sorbitol dehydrogenase) - fructose is the fuel of sperm
In DM, there is excess glucose which is converted into sorbitol.The lens and nerves lack sorbitol dehydrogenase. Sorbitol accumulates and causes
cataract formation and peripheral neuropathy
Produces NADPH and ribose 5-P, metabolic use of 5-carbon sugars
Pentose Phosphate Pathway/Hexose Monophosphate Shunt
NADPH provides electrons for
FA and steroid biosynthesis reduction of glutathione cytochrome P450 WBC respiratory burst nitric oxide synthesis
Pentose Phosphate Pathway: Location
Cytoplasm, liver, adipose, adrenals, thyroid, testes, RBC, lactating mammaries (high in tissue that produces lipids, low in skeletal muscle and non-lactating mammaries)
Pentose Phosphate Pathway: Substrates
glucose 6-P
Pentose Phosphate Pathway: Products
ribose 5-P
fructose 6-P
glyceraldehyde 3-P
NADPH
Pentose Phosphate Pathway: Rate-Limiting Step
glucose 6-P → 6-phosphogluconate
Pentose Phosphate Pathway: Rate-Limiting Enzyme
glucose 6-P dehydrogenase
Catalyzed by glucose 6-P dehydrogenase
glucose 6-P → 6-phosphogluconate
Pentose Phosphate Pathway: Phase 1
oxidative, irreversible
Pentose Phosphate Pathway: Phase 2
non-oxidative, reversible
Pentose Phosphate Pathway: Phase 1 Enzyme
glucose 6-P dehydrogenase
Pentose Phosphate Pathway: Phase 2 Enzyme
transketolases (requires thiamine)
Pentose Phosphate Pathway: Phase 1 Products
2 NADPH
6-phosphogluconate
Pentose Phosphate Pathway: Phase 2 Products
ribose 5-P, glyceraldehyde 3-P, fructose 6-P
RBC transketolase activity can be used to diagnose
thiamine deficiency
Reduced _____ removes H2O2 in a reaction catalyzed by _____.
reduced glutathione (G-SH), glutathione peroxidase
Reacting with H2O2 oxidizes _____ but only reduced _____ can remove H2O2.
oxidized glutathione (G-S-S-G), glutathione
Reduced glutathione sequesters harmful H2O2
glutathione peroxidase
Glutathione peroxidase cofactor
Se - selenium
Reduced glutathione is recreated using NADPH
glutathione reductase
Most common disease producing enzyme abnormality in humans
Glucose 6-Phosphate Deficiency (G6PD)
Decreased NADPH in RBCs and decreased activity of glutathione reductase causing hemolytic anemia due to poor RBC defense against free radicals and peroxides, neonatal jaundice 1-2 days after birth
Glucose 6-Phosphate Deficiency (G6PD)
Precipitating factors for G6PD
Oxidative Stressors: infection (most common), drugs (AAA) - antibiotics (sulfonamides, chloramphenicol), antimalarials (primaquine), anti-pyretics (except ASA and paracetamol, fava beans
Altered hemoglobin precipitates within RBCs found in G6PD
Heinz BOdies
Altered RBcs due to phagocytic removal of Heinz bodies in the spleen
Bite cells
Converts molecular oxygen into superoxide in leukocytes (especially neutrophils and macrophages) and used in the respiratory burst that kills bacteria
NADPH oxidase
Deficiency in NADPH oxidase leading to severe, persistent and chronic pyogenic infections caused by catalase (+) bacteria
Chronic Granulomatous Disease
