Carbohydrates Flashcards
CARBOHYDRATE METABOLISM
What is the rate-limiting step of glycolysis?
Citric acid cycle (TCA)?
Gluconeogenesis?
PhosphoFructoKinase-1 (PFK-1) in GlycoLysis
TCA: IsoCitrate Dehydrogenase
Fructose 1, SIx BisPhosphate in GlucoNeogenesis
“_P_apa _F_ranz _K_issed _1_ girl → _G_e_L_a
_T_e_CA_… _I_ _C_ee _D_isappointment
_F_ranz _1_s _S_Ingle → _B_asta _P_uro _G_V _N_a”
What is the rate-limiting step of the citric acid cycle (TCA)?
TCA: IsoCitrate Dehydrogenase
*“Papa Franz Kissed 1 girl → GeLa *
*TeCA… I Cee Disappointment *
Franz 1s SIngle → Basta Puro GV Na”
What is the rate-limiting step of gluconeogenesis?
Fructose 1, SIx BisPhosphate in GlucoNeogenesis
“_F_ranz _1_s _S_Ingle → _B_asta _P_uro _G_V _N_a”
What is the rate-limiting step of glycogenesis?
Glycogen Synthase
What is the rate-limiting step of glycogenolysis?
Glycogen Reductase
What are the functions of Carbohydrates? (4)
- energy source
- storage form of energy
- part of cell membranes
- structural components
What are the most abundant organic molecules in nature?
Carbohydrates
How are carbohydrates classified?
Carbohydrates are classified according to number of sugar units.
What are carbohydrates composed of?
Carbohydrates are polymers of repeating sugar units.
What are the simplest carbohydrates and the number of sugar units they possess?
Monosaccharides have 1 sugar unit hence cannot be hydrolysed further
How are monosaccharides classified?
Monosaccharides are classified according to MUNBER OF CARBON atoms and their MOST FUNCTIONAL group.
What monosaccharides have a carbonyl group at the end?
ALDOSES have a carbonyl group at the end
What monosaccharides have a carbonyl group in the middle?
KETOSES have a carbonyl group in the middle
What monosaccharides have 5 carbon atoms?
PENTOSES have 5 carbon atoms
What monosaccharides have 6 carbon atoms?
HEXOSES have 6 carbon atoms
What is the reduced form of glucose?
Its oxidised form?
reduced → SORBITOL (alcohol)
oxidized → GLUCORONIC ACID (acid)
What monosaccharides are in nucleic acids?
RIBOSE is found in nucleic acids
What monosaccharides are in glycoproteins?
XYLOSE, ARABINOSE, & MANNOSE are found in glycoproteins
What monosaccharides are in proteoglycans?
NEURAMINIC ACID is found in proteoglycans
What monosaccharides are in cardiac tissue?
LYXOSE is found in cardiac tissue
What are condensation products of 2 monosaccharide units?
Disaccharides are condensation products of 2 monosaccharide units
Of what importance is LYXOSE? What is its classification?
LYXOSE is a monosaccharide found in cardiac tissue.
How are sugar units linked in disaccharides?
Disaccharides are linked by glycosidic bonds
What is the product of 2 glucose molecules linked by a glycosidic bond?
What kind of glycosidic bond?
Maltose is 2 glucose molecules linked by a α(1→4) glycosidic bond.
What is the product of a glucose and galactose molecules linked by a glycosidic bond?
What kind of glycosidic bond?
Lactose is 1 glucose and 1 galactose molecule linked by a β(1→4) glycosidic bond.
What is the product of a glucose and a fructose molecule linked by a glycosidic bond?
What kind of glycosidic bond?
Sucrose is 1 glucose and 1 fructose molecule linked by a α1→β2 glycosidic bond.
What disaccharidase deficiency will lead to diarrhea and flatulence?
Lactase or Sucrase deficiency.
What are condensation products of 3-10 monosaccharides? Give an example.
Oligosaccharides are condensation products of 3-10 monosaccharides. Ex. Maltotriose
What are condensation products of >10 monosaccharide units? Give an example.
Polysaccharides are condensation products of >10 monosaccharide units. Ex. Starch,* *_Glycogen_, Inulin,* *_Cellulose_, Chitin
True or False:
Most oligosaccharides are digested by human enzymes.
False.
Most oligosaccharides are NOT digested by human enzymes. Others can be only partially digested by humans.
What is the function of oligosaccharides if most are NOT digested by human enzymes and others can be only partially digested by humans?
The undigested portion serves as food for the intestinal microflora. Depending on the type of oligosaccharide, different bacterial groups are stimulated or suppressed.
The Sialyl-Lewis x Oligosaccharide is the most abundant carbohydrate receptor present in the outer coating (zona pellucida) of the human ova, and is implicated as a large factor of Sperm-ZP binding leading to fertilization.
What is a homopolymer of glucose forming an α-glycosidic chain? What do you call this chain?
STARCH is a homopolymer of glucose forming an α-glycosidic chain called glucan or glucosan.
What is the storage polysaccharide in animals, sometimes called ANIMAL STARCH?
GLYCOGEN is the storage polysaccharide in animals, sometimes called ANIMAL STARCH.
What is a polysaccharide of fructose used to determine GFR?
Inulin a polysaccharide of fructose used to determine GFR.
What kind of chain and branching glucosidic linkages are found in glycogen?
Glycogen forms chains of 12-14 α-D-glucopyranose residues in a α1→4 glucosidic linkage with branching through a α1→6 glucosidic bond.
What glucosidic linkages are found in glycogen chains?
Glycogen forms chains of 12-14 α-D-glucopyranose residues in a α1→4 glucosidic linkage.
What glucosidic linkages are found in glycogen branches?
Glycogen forms branching through a α1→6 glucosidic bond.
What polysaccharide is the chief constituent of plant cell walls?
Cellulose is the chief constituent of plant cell walls.
What is cellulose composed of?
What is its solubility?
Cellulose is consists of β-D-glucopyranose units linked by β1→4 bonds to form long straight chains strengthened by cross-linking hydrogen bonds. It is insoluble and cannot be digested by mammals.
Why can’t mammals digest cellulose?
Mammals only possess α-glucosidases that cleave α-glucosidic linkages hence dietary fibers cannot be digested and are passed in stool (ex. kangkong, corn)
What is the structural polysaccharide in the exoskeleton of crustaceans and insects?
Chitin is the structural polysaccharide in the exoskeleton of crustaceans and insects.
Of what diagnostic use is Inulin?
Inulin is used to determine GFR.
What are complex carbohydrates containing amino sugars and uronic acids? Examples?
Glycosaminoglycans are complex carbohydrates containing amino sugars and uronic acids.
Ex. hyaluronic acid, chondroitin sulfate, heparin
What is a glycosaminoglycan attached to a protein molecule?
Proteoglycans are glycosaminoglycans attached to a protein molecule
Glycosaminoglycans were formerly known as?
Glycosaminoglycans were formerly known as mucopolysaccharides
Glycoproteins were formerly known as?
Glycoproteins were formerly known as mucoproteins
What are proteins containing branched or unbranched oligosaccharide chains?
Glycoproteins are proteins containing branched or unbranched oligosaccharide chains.
What are isomers?
Isomers are compounds that have the same chemical formula but different structures.
What are epimers?
Epimers are compounds that differ in configuration around one one specific carbon atom (except the carbonyl carbon)
What are the epimers of α-D-glucose?
α-D-glucose & α-D-galactose are epimers at C4.
α-D-glucose & α-D-mannose are epimers at C2.
At which carbon is α-D-glucose & α-D-galactose epimers?
α-D-glucose & α-D-galactose are epimers at C4.
At which carbon is α-D-glucose & α-D-mannose epimers?
α-D-glucose & α-D-mannose are epimers at C2.
What are Enantiomers?
Enantiomers are pairs of structures that are mirror images of each other.
What are the subtypes of enantiomers?
Levo-rotatory (left-handed) and Dextro-rotatory (right-handed)
What enantiomer is the major sugar in humans?
D-glucose
What are epimers at C4?
α-D-glucose & α-D-galactose are epimers at C4
What are epimers at C2?
α-D-glucose & α-D-mannose are epimers at C2.
What are anomers?
Anomers are sugars that are convertible between linear and ring form.
Which anomer is more common?
Cyclic or ring forms are more common anomers.
What is formed in the ring anomer?
The ring form results in the formation of the anomeric carbon.
What are the subtypes of anomers?
Anomers are designated as α and β configurations of the sugar.
What is the process wherein α and β forms spontaneously interconvert in a solution? Which form is predominant?
Mutarotation is the process wherein α and β forms spontaneously interconvert in a solution. In a solution, α and β forms are in EQUILIBRIUM.
In a Haworth projection, how many carbons are in a furan ring?
A furan ring is a 5 carbon ring.
In a Haworth projection, how many carbons are in a pyran ring?
A pyran ring is a 6 carbon ring.
What are the principle sites of carbohydrate digestion?
The principle sites of carbohydrate digestion are the mouth and intestinal lumen.
Digestion of carbohydrates are generally completed by time the food reaches where?
Digestion of carbohydrates are generally completed by time the food reaches the junction of the duodenum and jejunum.
Where does carbohydrate digestion begin? Physical digestion? Chemical digestion?
Carbohydrate digestion begins during mastication in the mouth.
Physical digestion = mastication
Chemical digestion = salivary amylase
What does pancreatic amylase hydrolyse?
Pancreatic amylase hydrolyses complex carbohydrates to disaccharides and trisaccharides but not directly to monosaccharides.
What enzyme completes the digestive process?
Where are they located?
Give examples.
Disaccharidases in the brush border complete the digestive process.
Ex. isomaltase, maltase, lactase, sucraase
What type of glycosidic bonds can amylase digest?
Amylase can only digest α(1→4) glycosidic bonds.
What glucose transporter is located in the luminal side of the intestinal epithelium?
What sugars?
By what transport mechanism?
GLUT-5 transports glucose, galactose, and fructose from the lumen into the cell via facilitated diffusion.
“GLUT-5 = LUMEN has 5 letters”
What glucose transporter is located in the basement membrane of the intestinal epithelium?
What sugars?
By what transport mechanism?
GLUT-2 transports ALL sugars from the cell into the blood via facilitated diffusion.
“GLUT-2 = BM has 2 letters”
What transporter is located in the luminal side of the intestinal epithelium?
What sugars?
By what transport mechanism?
SGLT-1 (Sodium Glucose LUMINAL Transporter-1) transports glucose and galactose ONLY from the lumen into the cell via secondary active transport. SGLT-1 is a Na-hexose symporter.
What monosaccharide is absorbed and secreted by the intestinal epithelium purely by facilitated diffusion?
Fructose
What monosaccharides is absorbed by facilitated diffusion AND secondary active transport?
Glucose and Galactose
What transporters are found on the luminal side of the intestinal epithelium?
GLUT-5 and SGLT-1
What transport is found on the basement membrane of the intestinal epithelium?
**GLUT-2 **is found on the basement membrane of the intestinal epithelium
What is the rationale behind administering glucose in ORS? Why is ORS-75 best for absorption?
SGLT-1 is a Na-hexose symporter therefore in order to enhance the absorption of sodium it must be transported with glucose. ORS-75 has equal moles of Na and glucose (75 mEq/l sodium, 75 mmol/l glucose)
What is the increase of blood glucose after a test dose of a carbohydrate compared with that after an equivalent amount of glucose?
The Glycemic Index is increase of blood glucose after a test dose of a carbohydrate compared with that after an equivalent amount of glucose.
What will tell you how fast a carbohydrate is absorbed?
The Gylcemic Index will tell you how fast a carbohydrate is absorbed.
What is the absorption of a carbohydrate with a glycemic index > 1?
A carbohydrate with a glycemic index > 1 has a fast absorption.
What is the absorption of a carbohydrate with a glycemic index < 1?
A carbohydrate with a glycemic index < 1 has a slow absorption.
Food with what glycemic index is recommended for DM and dieting? Why?
Food with LOW glycemic index is beneficial to DM and dieting
- prevents rapid rises in blood glucose
- prevents rapid fluctuations in insulin secretion
In what state can acquired enzyme deficiency occur? Why? What should you advise your patient?
Acquired enzyme deficiency occurs during severe diarrhea because the enzymes are removed in stool.
Advise patients with AGE to avoid dairy products.
What is the sum of all the chemical reactions in a cell, tissue, or the whole body?
Metabolism is the sum of all the chemical reactions in a cell, tissue, or the whole body.
What kind of metabolic pathway yields synthesis of compounds from smaller raw materials? Give examples.
Anabolic pathways or Anabolism yields synthesis of compounds from smaller raw materials hence it is endergonic and divergent.
Ex. protein & triglyceride synthesis, glycogenesis
What kind of metabolic pathway results in the breakdown of larger molecules? Give examples.
Catabolic pathways or Catabolism results in the breakdown of larger molecules hence it is exergonic and convergent.
Ex. glycolysis, beta-oxidation, glycogenolysis
What are the usual reactions and products of catabolism?
Catabolism produces reducing equivalents and ATP (mainly via the respiratory chain) usually through oxidative reactions.
What are the crossroads of metabolism? Give an example.
Amphibolic pathways is the link between anabolic and catabolic pathways.
Ex. TCA (Kreb’s) cycle
What are the regulators of metabolism?
Regulators of Metabolism
- Signals within the cell
- communication between cells
- second messenger systems
How can signals within the cell regulate metabolism?
- substrate availability
- product inhibition
- allosteric activators or inhibitors
How can communication between cells regulate metabolism?
- through direct contact via gap junctions
- through synaptic signalling via NT
- through endocrine signalling via hormones
What are examples of second messenger systems? Give examples of each.
- Calcium/inositol triphosphate (IP3): epinephrine
- Adenylyl cyclase system (cAMP): glucagon, epinephrine
- Guanylate cyclase system (cGMP): ANP, NO
What are membrane-bound enzymes that converts ATP to cyclic AMP in response to hormones?
Adenylyl cyclase system
What enzyme is responsible for the formation of cAMP?
Adenylate cyclase
What enzyme is responsible for the degradation of cAMP?
cAMP phosphodiesterase degrades cAMP
What G-protein stimulates adenylate cyclase?
What happens to cAMP?
Gs stimulates adenylate cyclase hence decreases cAMP
What G-protein inhibits adenylate cyclase?
What happens to cAMP?
Gi inhibits adenylate cyclase hence increases cAMP
What are the GLUT transporters found in the brain and placenta?
GLUT 1 & 3 are found in the brain and placenta
“1 and 3 put side by side looks like a B (remember P almost looks like i too)”
What are the GLUT transporters found in the kidney?
GLUT 1, 2 & 3 are found in the kidney
“Kindergarden kid(ney)s learn 1,2,3”
What GLUT transporter requires insulin for the uptake of glucose?
What tissues possess them?
GLUT-4 requires insulin for the uptake of glucose therefore will be found in tissue where it can be stored such as SKELETAL & CARDIAC MUSCLE and ADIPOSE.
What GLUT transporter absorbs glucose into the body?
What tissue possesses them?
GLUT-5 is found in the luminal side of the small intestines and absorbs glucose into the body
What GLUT transporter does not require insulin?
What tissues possess them?
GLUT-2 does not require insulin therefore will be found in tissues that need to detect glucose levels such as the LIVER, PANCREATIC B-CELL (as a stimulus to release insulin), KIDNEY, and SMALL INTESTINE
What GLUT transporter is found in skeletal muscles, cardiac muscles and adipose?
Skeletal muscles, cardiac muscles and adipose store glucose (or its derivatives) therefore they possess GLUT-4 which requires insulin for the uptake of glucose.
High-yield GLUT
Brain?
Insulin-stimulated?
Insulin-independent?
Glucose absorption?
High-yield GLUT
Brain = GLUT 1 & 3 (looks like B)
Insulin-stimulated = GLUT-4 (storage so in muscle and fat)
Insulin-independent = GLUT-2 (level detector so in pancreas, liver, kidney, SI)
Glucose absorption = GLUT-5 (lumen of SI so for absorption)
What is glycolysis for?
It is the major pathway for glucose metabolism that converts glucose into 3-carbon compounds to provide energy
Where does glycolysis occur? What part of the cell?
Glycolysis occurs in the CYTOPLASM of ALL cells
What is the substrate and end-products of glycolysis?
Substrate
= glucose
Products
= 2 pyruvate (aerobic) or 2 lactate (anaerobic)
Aerobic glycolysis is dependent on the presence of what? (2)
Aerobic glycolysis is dependent on:
- presence of mitochondria
- availability of oxygen
What is the rate-limiting step of glycolysis?
PhosphoFructoKinase-1 (PFK-1) in GlycoLysis
“Papa Franz Kissed 1 girl → GeLa”
What is the end-product of aerobic glycolysis?
pyruvate
What is the end-product of anaerobic glycolysis?
lactate
What are the 2 stages of glycolysis?
What are their products?
How many ATP or NADH are consumed or generated?
Energy Investment - energy is used up to produce phosphorylated intermediates (2 ATP is consumed)
Energy Generation - ATP is produced through substrate-level phosphorylation (4 ATP and 2 NADH generated)
What are the important steps in glycolysis?
Are they reversible? Regulated?
The 3 irreversible and regulated steps in glycolysis are:
Step 1: phosphorylation of glucose
Step 3: phosphorylation of fructose-6-phosphate
Step 10: formation of pyruvate
What are the 2 isoenzymes that phosphorylate glucose to glucose-6-phosphate?
Hexokinase & Glucokinase
Hexokinase vs. Glucokinase: tissues?
Hexokinase: present in most tissues
Glucokinase: only in liver and islet cells of the pancreas
Hexokinase vs. Glucokinase: inhibited by?
Hexokinase: inhibited by G-6-P
Glucokinase: inhibited by F-6-P
Hexokinase vs. Glucokinase: Km? affinity? Correlate.
Hexokinase: low Km so high affinity
(used by all cells even in fasting/low sugar levels)
Glucokinase: high Km so low affinity
(removes only the glucose in excess and converts it to storage form)
Hexokinase vs. Glucokinase: Vmax? Correlate.
Hexokinase: low Vmax so it is easily saturated then acts at a constant rate to provide only what the cell’s needs
Glucokinase: high Vmax so helps remove the glucose that is in excess of the cell’s needs
- “Glucokinase = eating at vikings”*
- “Hexokinase = eating skyflakes”*
Discuss the diagram in terms of Km, affinity, Vmax and correlates.
Hexokinase has a low Km and high affinity for glucose so it can be used by all cells even in fasting/low sugar levels. It has a low Vmax so it is easily saturated when blood glucose levels are high then acts at a constant rate to provide G-6-P for the cell’s needs.
Glucokinase has high Km and low affinity so it is active in high blood glucose levels (following a meal) to remove only the excess and convert it to G-6-P to be stored hence it is only found in the liver and pancreas. It has a high Vmax so it is not saturated at high glucose levels.
- “Glucokinase = eating at vikings*
- Hexokinase = eating skyflakes”*
What are the enzymes in STEP 1 of glycolysis?
What reaction does it catalyse?
Hexokinase & Glucokinase catalyses the phosphorylation of glucose to G-6-P.
What is the enzyme of STEP 3 of gylcolysis?
What reaction does it catalyse?
Phosphofructokinase-1 catalyzes phosphorylation of F6P to F-1,6-BP
***rate-limiting step of glycolysis
What is the enzyme in STEP 10 of glycolysis?
What reaction does it catalyse?
Pyruvate kinase catalyses the phosphorylation of phosphoenolpyruvate (PEP) to pyruvate
What are the 2 phosphofructokinases?
What are the reactions they catalyse?
Activators? Inhibitors?
PFK-1 converts F-6-P to F-1,6-P
- activated by F-2,6-BP and AMP
- inhibited by ATP and citrate
PFK-2 converts F-6-P to F-2,6-P
- activated by the well-fed state, increased insulin and decreased glucagon
- inhibited by reverse of its activators.
What is the activator of pyruvate kinase?
Pyruvate kinase is activated by F-1,6-BP (feedforward mechanism)
What is the inhibitor of pyruvate kinase?
increased glucagon and cAMP
What are the enzymes in the 2 steps that produce ATP in substrate-level phosphorylation?
ATP generating:
PhosphoGlycerATE Kinase
Pyruvate Kinase
“_AT_e,
Pakibukas ang GATE Kapag
Papasok si Kuya”
What are the enzymes in the 2 steps that produce NADH in substrate-level phosphorylation?
NADH generating:
GlyceraldeHYDE-3-Phosphate Dehydrogenase
“NAnay,
Go and HIDE sa TREE Pakipot kay Daddy”
What are the enzymes in the 3 energy-generating steps in substrate-level phosphorylation?
ATP generating:
“_AT_e, Pakibukas ang GATE Kapag Papasok si Kuya”
- PhosphoGlycerATE Kinase
- Pyruvate Kinase
NADH generating:
- “NAnay, Go and HIDE sa TREE Pakipot kay Daddy”*
- GlyceraldeHYDE-3-Phosphate Dehydrogenase
How many net molecules of ATP can be produced from 1 glucose molecule via substrate-level phosphorylation?
1 molecule of glucose will yield 4 ATP molecules via substrate level phosphorylation.
What are the 4 fates of pyruvate?
Fates of Pyruvate
- converted to LACTATE by lactate dehydrogenase in anaerobic glycolysis
- converted to ACETYL-CoA by pyruvate dehydrogenase in the citric acid cycle
- converted to OXALOACETATE by pyruvate carboxylase in gluconeogenesis
- converted to ETHANOL by pyruvate decarboxylase in fermentation (yeast)
What are the 2 possible outcomes of pyruvate in substrate-level phosphorylation?
What are the determinants of which outcome is favoured?
In aerobic glycolysis, pyruvate enters the citric acid cycle however there must be sufficient mitochondria and available oxygen. Lack thereof will preferentially convert pyruvate to lactate in anaerobic glycolysis.
What is the fate of NADH generated in aerobic glycolysis?
NADH proceeds to the Electron Transport Chain.
How is NADH and FADH transported into the impermeable inner mitochondrial membrane?
How many ATP will it yield per NADH?
NADH and FADH transported into the inner mitochondrial membrane via the
- Malate-Aspartate Shuttle: 1 NADH = 3 ATP
- **Glycerol-Phosphate Shuttle: **1 NADH = 2 ATP
Why will the Glycerol-Phosphate shuttle yield only 2 ATP vs. the 3 ATP yielded by the Malate-Aspartate Shuttle?
The final product of the Glycerol-Phosphate Shuttle is FADH2 will enter the TCA cycle in Complex II hence only 2 ATP are produced as opposed to the Malate-Aspartate Shuttle that produces ATP which binds to Complex I to produce 3 ATP.
What part of the cell can the ETC be found?
Mitochondria
Which mitochondrial membrane can the ETC be found?
INNER mitochondrial membrane
What is the fate of pyruvate in anaerobic glycolysis?
Pyruvate is reduced to Lactate by Pyruvate Dehydrogenase using 1 NADH.
What organs are strictly glycolytic (anaerobic glycolysis)?
RBC, Lens, Cornea, Kidney Medulla, Testes, WBC
“ReLi Can Kick My BALLS until its WHITE (when someone kicks you in the balls you can’t breathe so anaerobic”
What enzyme bypasses phosphoglycerate kinase in RBCs? What does it produce?
2,3-bisphosphoglycerate mutase bypasses phosphoglycerate kinase in RBCs to produce 2,3-BPG from 1,3-BPG.
When will increased levels of 2,3-BPG be found?
In conditions with low oxygen (ex. living in high altitudes) increased levels of 2,3-BPG be found
What type of poisoning inhibits pyruvate dehydrogenase by binding to lipoid acid and competes for inorganic phosphate as a substrate for glyceraldehyde-3-P-D?
Arsenic poisoning
- inhibits pyruvate dehydrogenase by binding to lipoid acid
- competes for inorganic phosphate as a substrate for glyceraldehyde-3-P-D
What is the treatment for arsenic poisoning?
Treat arsenic poisoning with chelation with dimercaprol or succimer
What is the pathophysiology of arsenic poisoning? Treatment?
Arsenic poisoning
- inhibits pyruvate dehydrogenase by binding to lipoid acid
- competes for inorganic phosphate as a substrate for glyceraldehyde-3-P-D
Treat with chelation with dimercaprol or succimer
What is the most common enzyme defect in glycolysis but only the 2nd MC enzyme deficiency causing hemolytic anemia?
Pyruvate Kinase Deficiency
- most common enzyme defect in glycolysis
- 2nd MC enzyme deficiency causing hemolytic anemia
How does pyruvate kinase deficiency cause chronic hemolytic anemia?
Pyruvate Kinase Deficiency lacks ATP which impairs the Na-K-ATPase pump without which intracellular gradient cannot be maintained and cell swelling and lysis will ensue.
What is the most common cause of intravascular hemolytic anemia? How can it be differentiated from PK deficiency?
The most common cause of intravascular haemolytic anemia is G6PD deficiency which has heinz bodies in the peripheral smear and a precipitating history of oxidative stress or “trigger”
(PK deficiency is the 2nd MC and lacks the said characteristics)
What is the most common oxidative stress that triggers G6PD deficiency?
The most common trigger is infection (other causes: drugs, fava beans)
What enzyme deficiency will manifest as low exercise capacity when on a high carbohydrate diet?
Muscle Phosphofructokinase Deficiency
What enzyme converts Pyruvate to Acetyl-CoA?
Pyruvate dehydrogenase complex
What are the co-factors of Pyruvate dehydrogenase? What is their source?
- Thiamine pyrophosphate (Vit B1)
- Lipoid acid
- Coenzyme A (contains Vit B5: pantothenic acid)
- FAD (from Vit B2: riboflavin)
- NAD+ (from Vit B3: niacin)
“Tender Loving Care For Nix”
What are the co-factors of the enzyme that converts Pyruvate to Acetyl-CoA?
- Thiamine pyrophosphate (Vit B1)
- Lipoid acid
- Coenzyme A (contains Vit B5: pantothenic acid)
- FAD (from Vit B2: riboflavin)
- NAD+ (from Vit B3: niacin)
“Tender Loving Care For Nix”
What are the 2 enzymes that require 5 cofactors?
ENZYMES
- Pyruvate Dehydrogenase
- α-KetoGlutarate Dehydrogenase
COFACTORS
- Thiamine pyrophosphate (Vit B1)
- Lipoid acid
- Coenzyme A (contains Vit B5: pantothenic acid)
- FAD (from Vit B2: riboflavin)
- NAD+ (from Vit B3: niacin)
“Pagka Depressed, Alejandrino Kuyas Give D’ Tender Loving Care For Nixor”
In order to enter the TCA cycle, what is the fate of pyruvate? What are the products?
Pyruvate is converted to Acetyl-CoA and will also produce NADH and CO2.
What is the most common biochemical cause of congenital lactic acidosis? Pattern of inheritance?
Pyruvate Dehydrogenase Deficiency is the most common biochemical cause of congenital lactic acidosis and is inherited as an X-linked dominant condition.
What enzyme deficiency leads to deprivation of Acetyl-CoA in the brain leading to psychomotor reiteration and death? How will you treat this patient?
Pyruvate Dehydrogenase Deficiency leads to deprivation of Acetyl-CoA in the brain leading to psychomotor reiteration and death. It is treated with a ketogenic diet.
Where does acquired pyruvate dehydrogenase deficiency occur? Its consequences? What vitamin is deficient?
Chronic alcoholism is an acquired pyruvate dehydrogenase deficiency. It leads to fatal pyruvic and lactic acidosis. Thiamine (Vit B1) is deficient.
What is the final common pathway for the aerobic oxidation of all nutrients? Alternate names(2)?
- TriCarboxylic Acid Pathway
- Kreb’s Cycle (eponym)
- Citric Acid Cycle
What is the TCA cycle for?
TCA cycle is amphibolic
- provides majority of the ATP for energy
- gluconeogenesis from skeletons of amino acids (malate)
- building blocks for amino acids and heme (succinyl CoA)
- fatty acid synthesis (citrate)
Where does the TCA occur? What part of the cell?
The TCA occurs in ALL cells with a mitochondria. It occurs in the mitochondrial matrix except for succinate dehydrogenase which is located in the inner mitochondrial membrane.
What is the substrate of the TCA cycle? products?
substrate = Acetyl Co-A
products = NADH, FADH2, GTP and CO2
Explain the TCA cycle (include enzymes and products)
“Cindy Is Kinky So She Fornicates Most Often”
What are the products of the TCA cycle if 1 glucose molecule was utilised?
Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: 2 ATP, 6 NADH2, 2 FADH2, 2 QH2 (ubiquinol) and 4 CO2.
What is the rate-limiting step of the citric acid cycle (TCA)?
TCA: IsoCitrate Dehydrogenase
“_T_e_CA_, I Cee Disappointment”
What TCA intermediate delivers acetyl-CoA to the cytoplasm for fatty acid synthesis?
What is this shuttle called?
Citrate delivers acetyl CoA to the cytoplasm for fatty acid synthesis via a citrate shuttle.
What TCA intermediate activates ketone bodies in extra hepatic tissues?
Succinyl CoA
What TCA intermediate is glycine added to to form D-ALA? What is it for?
Succinyl CoA and glycine make up D-ALA for a precursor for heme synthesis.
What TCA intermediate may be used for gluconeogenesis?
Malate
What hormone influences the TCA cycle? What are its effects?
NONE, there is no hormonal control for the TCA cycle.
In what step of the TCA cycle is new oxaloacetate synthesised?
NONE, the cycle does not synthesize NEW oxaloacetate.
How many ATPs are produced per 1 mole of acetyl CoA?
12 ATPs are produced per 1 mole of acetyl CoA
How many ATPs are produced per 1 mole of pyruvate?
15 ATPs are produced per 1 mole of pyruvate. Converting pyruvate to acetyl CoA will yield 1 additional NADH hence 3 ATPs via ETC (no shuttle because already in the mitochondria).
How many NADHs are produced per 1 mole of acetyl CoA? CO2?
3 NADH and 2 CO2
How many FADH2s are produced per 1 mole of acetyl CoA?
1 FADH2
How many NADHs are produced per 1 mole of pyruvate?
4 NADH and 3 CO2
How many GTPs are produced in the TCA cycle?
1 GTP
Which reactions release CO2 in the TCA cycle?
Isocitrate→ αKG →succinyl CoA by the enzymes ICD and αKGD respectively
- ***these rxns also yield NADH*
- ****also pyruvate→acetyl CoA catalysed by PD (the step before entering TCA)*
Which reactions reduce NAD to NADH in the TCA cycle?
Isocitrate→ αKG →succinyl CoA by the enzymes ICD and αKGD respectively as well as malate→OAA catalysed by MD
***these rxns also yield CO2
Which reaction reduces FAD to FADH in the TCA cycle?
Succinate→Fumarate catalysed by SD
Which reaction reduces GDP to GTP in the TCA cycle?
Succinyl CoA→Succinate catalysed by STK reduces GDP to GTP
What is gluconeogenesis for?
Gluconeogenesis is for the production of glucose from the ff intermediates:
- intermediates of glycolysis and TCA
- glycerol from TAGs
- lactate from the Cori Cycle
- carbon skeletons (α-ketoacids) of glycogenic amino acids
Where does gluconeogenesis occur? What part of the cell?
Gluconeogenesis occurs in the liver (90%) and kidneys (10%). It occurs in BOTH the mitochondria and cytoplasm.
What pathways occur in BOTH mitochondria and cytoplasm?
“HUG”
- Heme synthesis
- Urea cycle
- Gluconeogenesis
During prolonged fasting, what is the percentage of kidney gluconeogenesis?
Kidneys contributed as much as 40% (from 10%)
What is the substrate and product of gluconeogenesis?
The substrate of gluconeogenesis is pyruvate and its product is glucose.
What is the rate-limiting step of gluconeogenesis?
Fructose 1, 6 (SIx) BisPhosphate in GlucoNeogenesis
“Franz 1s SIngle - Basta Puro GV Na”
What is the Cori Cycle?
In the Cori Cycle, the lactate generated during anaerobic metabolism is brought to the liver where it is converted to glucose by hepatic gluconeogenesis then brought back to the muscles and RBC.
What is the energy expenditure of the Cori Cycle?
The Cori Cycle utilises 4 ATPs.
What are the important steps in gluconeogenesis?
3 irreversible steps in gluconeogenesis** **(reverse of glycolysis):
Step 10: pyruvate → OAA → PEP
Step 3: dephosphorylation of F-1,6-BP to F-6-P
Step 1: dephosphorylation of G-6-P to glucose
What enzymes catalyse Step 10: pyruvate → OAA → PEP?
What glycolytic enzyme does it reverse?
What do the enzymes require?
Step 10 has 2 reactions that reverse Pyruvate Kinase:
- pyruvate → OAA is catalysed by pyruvate carboxylase which requires biotin and ATP
- OAA → PEP is catalysed by PEP carboxykinase which requires GTP.
Where is GTP mostly produced?
GTP is mostly produced in the β-oxidation of fats hence patients with deficient fat metabolisms have problems in gluconeogenesis.
What class of enzymes attach a carbon atom using CO2 as a substrate? Give 3 examples and the pathways they are involved in.
Carboxylases:
- pyruvate carboxylase (gluconeogenesis)
- acetyl CoA carboxylase (fatty acid synthesis)
- propionyl CoA carboxylase (β-oxidation of fatty acids with odd # of carbons)
What is the co-factor of carboxylases?
Carboxylases require BIOTIN as a co-factor.
What enzyme catalyses Step 3: F-1,6-BP → F-6-P?
What glycolytic enzyme does it reverse?
What activates and inhibits the enzyme?
Step 3 reverses PFK-1:
F-1,6-BP → F-6-P is catalysed by fructose-1,6-bisphosphatase
- activated by ATP
- inhibited by F-2,6-P and AMP
What are the 2 functions of F-2,6-BPase?
- promotes glycolysis by activating PFK-1
- inhibits gluconeogensis by inhibiting F-1,6-BPase
What enzyme catalyses Step 1: G-6-P → glucose?
What glycolytic enzyme does it reverse?
Step 1 reverses hexokinase & glucokinase:
G-6-P → glucose is catalysed by G-6-Pase.
Apart from gluconeogenesis, what other pathway shares the final step, G-6-P → glucose?
Gluconeogenesis and glycogenolysis share the final step, G-6-P → glucose.
In what organs do the reaction G-6-P → glucose catalysed by G-6-Pase occur? What is its significance?
G-6-P is converted to glucose by G-6-Pase in the liver and kidneys only.
Muscle lacks this enzyme hence G6P cannot be transported across the cell membrane without being dephosphorylated. Therefore, glycogen stored within it can only be utilized by muscle.
How is gluconeogenesis regulated?
_Regulation of Gluconeogenesis _
- circulating levels of glucagon
- viability of glycogenic substances
- allosteric activation by acetyl CoA
- allosteric inhibition by AMP
What is the energy expenditure of gluconeogenesis?
gluconeogenesis uses 4 ATP, 2 GTP and oxidises 2 NADH back to NAD+
What is the blood glucose concentration that exceeds renal threshold? What is its consequence?
If blood glucose concentration exceeds 9.5-10 mmol/L (300mg/dL), glycosuria occurs. Glucosuria is when the glomerular filtrate contains more glucose than can reabsorbed hence will appear in urine.
Why does hypoglycemia occur in alcoholism?
In alcoholism, high amounts of NADH is formed by alcohol dehydrogenase and acetaldehyde dehydrogenase.
High amounts of NADH favors the ff rxns:
- pyruvate → lactate
- OAA → malate
- DHAP → glycerol-3-P
What is the expected blood glucose abnormalities in pregnancy?
- high fetal consumption and hyperinsulinemia (due to high estrogen) causes fasting hypoglycemia
- elevated HPL causes insulin resistance hence postprandial hyperglycemia
What causes hypoglycemia in neonates?
- LBW and premature babies have little adipose tissues.
- enzymes of gluconeogenesis of neonates are not yet completely functional
What is the major storage carbohydrate in animals?
Glycogen
What glycosidic bonds are used in glycogen for elongation?
α(1→4) glycosidic bonds for elongation
What glycosidic bonds are used in glycogen for branching?
α(1→6) glycosidic bonds for branching
Where is glycogen stored?
Liver (100g = 6%) and muscle (400g = <1%) ONLY
What is glycogen?
Glycogen is a branched polymer of glucose used for storage of carbohydrates in animals.
Why is muscle glycogen intended for internal use only while liver glycogen is destined for transport?
Muscle glycogen lacks G6Pase.
What is glycogenenesis for?
Glycogenesis synthesizes new glycogen molecules from α-D-glucose for storage of carbohydrates
Where does glycogenesis occur? In which part of the cell?
Glycogenesis occurs in the liver and muscle. It occurs in the cytosol.
What are the substrates in glycogenesis? The product?
SUBSTRATES
= UDP-glucose, ATP, UTP and glycogenin (the core primer protein)
PRODUCT
= glycogen
What is the rate-limiting step of glycogenesis?
The rate-limiting step of glycogenesis is the elongation of glycogen through the addition of α(1→4) glycosidic bonds by glycogen synthase.
What are the important steps in glycogenesis?
Important steps in glycogenesis
- G6P→G1P catalysed by phosphoglucomutase
- synthesis of UDP-glucose by UDP-glucose phosphorylase
- elongation of glycogen chains by glycogen synthase
- formation of branches in glycogen by the branching enzyme
What enzyme is responsible for the elongation of glycogen chains? What is its MOA?
Glycogen synthase elongates glycogen chains through the addition of α(1→4) glycosidic bonds at the non-reducing end (carbon 4) of glucose residues.
What enzyme is responsible for the formation of branches in glycogen? What is its MOA?
Branching enzyme forms branches in glycogen through the addition of new α(1→6) glycosidic bonds and transferring 5-8 glucosyl residues
What are the substrates for the synthesis of the activated glucose, UDP-glucose?
glucose-1-P and UTP
What is glycogenolysis for?
Glycogenolysis shortens glycogen chains to produce molecules of α-D-glucose
Where does glycogenolysis occur? In what part of the cell?
Glycogenolysis occurs in liver and muscle. Its occurs in the cytosol.
What are the substrates and products of glycogenolysis?
SUBSTRATE
= glycogen
PRODUCTS
= G-1-P and free glucose (produced during the debranching process)
How does the glycogenolysis differ in the liver and muscle?
The liver can release free glucose to the circulation while the muscle is limited to G-6-P which will be confined in the muscle solely for its own use.
What is the rate-limiting step in glycogenolysis?
The rate-limiting step in glycogenolysis is the removal of glucose by the breaking α(1→4) bonds by glycogen phosphorylase
What are the enzymes that catalyse the removal of branches in glycogenolysis? What are their actions? Products released?
debranching enzyme α(1→4)→α(1→4) glucantransferase transfers the limit dextrin
amylo-α(1→6) glucosidase removes a free glucose by breaking the α(1→6) bond
PRODUCTS: free glucose from the breakage of the α(1→6) bond
What enzyme catalyses the reaction G1P→G6P? What is the significance of this step?
phosphoglucomutase catalyses the reaction G1P→G6P. This is the final step in glycogenolysis in the muscle while the liver further converts G6P to glucose through the enzyme G-6-Pase.
What is the enzyme responsible for the lysosomal degradation of glycogen? What disease is linked to its deficiency?
α(1→4) glucosidase or acid maltase degrades lysosomal glycogen and its deficiency leads to lysosomal accumulation of glycogen (Pompe’s disease or GSD type II)
What are inherited disorders characterised by deposition of abnormal type or quantity of glycogen in tissues? How many types are there?
GLYCOGEN STORAGE DISEASES are a group of inherited disorders characterised by deposition of abnormal type or quantity of glycogen in tissues. There are 12 types total, all of which are enzyme deficiencies.
What GSD (type and eponym) is characterised by hepatomegaly, renal enlargement, hypoglycemia, lactic acidosis/ketosis?
**GSD type I : Von Gierke’s Disease **is characterised by hepatomegaly, renal enlargement, hypoglycemia, lactic acidosis/ketosis
What is the enzyme deficient in GSD type I?
What is its eponym?
Pathophysiology?
What are the usual findings?
GSD type I : Von Gierke’s Disease is deficient in G-6-Pase, lack of which inhibits final steps of glycogenolysis and gluconeogenesis and leads to accumulation. This results in severe hypoglycemia. Phosphorylated glucose cannot leave the hepatocyte and kidney (hepatic & renal enlargement) so an increase in glycolytic pathway metabolites occurs and are metabolized into lactate (lactic acidosis). Glucose is also shunted into making more triglycerides, causing an increase in LDL and VLDL which will lead to β-oxidation → ketogenesis → ketosis.
What GSD (type and eponym) is characterised by milder manifestations of hepatomegaly, splenomegaly, progressive weakness, muscle wasting of interossei? What other GSD does it mimic?
GSD type III : Forbes-Cori’s Disease manifests as hepatomegaly, splenomegaly, progressive weakness, muscle wasting of interossei. Its manifestations are a milder form of GSD type I but unlike GSD I, kidney enlargement is not observed.
What is the enzyme deficient in GSD type III?
What is the eponym?
Pathophysiology?
Usual findings?
GSD type III : Forbes-Cori’s Disease is deficient in debranching enzyme which causes the body to form glycogen molecules that have an abnormal structure. Its manifestations are hepatomegaly, splenomegaly, progressive weakness, and muscle wasting of interossei. Its manifestations are a milder form of GSD type I but unlike GSD I, kidney enlargement is not observed.
What GSD (type and eponym) is characterised by hepatic failure, cirrhosis, hepatosplenomegaly, cardiomyopathy, failure to thrive, hypotonia, and ventricular arrhythmias? What other GSD does it mimic?
GSD type IV : Andersen’s Disease or Amylopectinosis is characterised by hepatic failure, cirrhosis, hepatosplenomegaly, cardiomyopathy, failure to thrive, hypotonia, and ventricular arrhythmias. Its manifestations are a severe form of GSD type I.
What is the enzyme deficient in GSD type IV?
What is the eponym?
Pathophysiology?
Usual findings?
GSD type IV : Andersen’s Disease or Amylopectinosis is deficient in branching enzyme leading to a cytoplasmic accumulation of dextrin (unbranched glycogen). Deficiency relates to liver disease and include hepatic failure, cirrhosis, hepatosplenomegaly, cardiomyopathy (less frequent), failure to thrive, hypotonia and ventricular arrhythmias. Its manifestations are a severe form of GSD type I.
What GSD (type and eponym) is characterised by cardiomegaly & heart failure, macroglossia, asymmetry of affected muscle groups, limb-girdle weakness, and respiratory muscle involvement?
GSD type II : Pompe’s Disease is characterised by cardiomegaly, heart failure, macroglossia, asymmetry of affected muscle groups, and limb-girdle weakness. Respiratory muscle involvement and cardiomegaly is a hallmark of Pompe’s disease.
What is the enzyme deficient in GSD type II?
What is the eponym?
Pathophysiology?
Usual findings?
GSD type II : Pompe’s Disease is deficient in acid maltase which results in accumulation of structurally normal glycogen in lysosomes which may interrupt normal functioning of other organelles. It is characterised by heart failure, macroglossia, asymmetry of affected muscle groups and limb-girdle weakness. Respiratory muscle involvement and cardiomegaly is a hallmark of Pompe’s disease.
What GSD (type and eponym) is characterised by cramps, fatigue, exercise intolerance, progressive proximal weakness, “second-wind” phenomenon and myoglobinuria without lactic acidosis?
GSD type V : McArdle’s Disease is characterised by cramps, fatigue, exercise intolerance, progressive proximal weakness, “second-wind” phenomenon and myoglobinuria without lactic acidosis
What is the enzyme deficient in GSD type V?
What is the eponym?
Pathophysiology?
Usual findings?
GSD type V : McArdle’s Disease is deficient in skeletal muscle glycogen phosphorylase. With intense exercise, glucose from glycogen stores in muscle becomes the predominant resource and fatigue develops when the glycogen supply is exhausted hence it is characterised by cramps, fatigue, pain after exercise, progressive proximal weakness, and “second-wind” phenomenon. Myoglobinuria without lactic acidosis may result from the breakdown of skeletal muscle known as rhabdomyolysis (often provoked by a bout of exercise). In the long term, patients may exhibit renal failure due to the myoglobinuria, and with age, patients may exhibit progressively increasing weakness and substantial muscle loss.Hypoglycemia is not an expected finding because liver phosphorylase is not involved.
What is the “second wind” phenomenon?
What disease is it unique to?
GSD type V : McArdle’s Disease may exhibit a “second wind” phenomenon, characterized by better tolerance for aerobic exercise after approximately 10 minutes.If a patient nearing fatigue slows exercise to a tolerable level, a point exists at which exercise may be increased again without previous symptoms. This is attributed to the combination of increased recruitment of motor units, increased cardiac output & blood flow and the ability of the body to find alternative sources of energy, like fatty acids and proteins.
What is an important source of galactose?
Dissacharide lactose in milk is an important source of galactose.
What are the monosaccharides in lactose?
What is its dietary source?
What enzyme hydrolyses it and where?
Lactose = glucose + galactose (milk and dairy products)
hydrolysed by lactase in the intestinal brush border
True or False:
Pancreatic amylase can hydrolyse disaccharides and trisaccharides.
False. Only disaccharidases and trisaccharidases can.
Hexokinase vs. Glucokinase: greater affinity for glucose?
Hexokinase has a greater affinity for glucose (lower Km)
What are the important steps in Galactose Metabolism?
Important steps in Galactose Metabolism
- Phosphorylation of galactose to galactose-1-P by galactokinase and hexokinase
- Formation of UDP-galactose from Gal-1-P and UDP-glucose by Gal-1-P uridyl transferase
- Use of galactose as a carbon source by converting UDP-galactose to UDP-glucose by the enzymes UDP-hexose-4-epimerase
What enzyme deficiency causes cataracts in early childhood, galactosemia and galactosuria?
Galactokinase deficiency causes cataracts in early childhood, galactosemia and galactosuria
What enzyme deficiency causes cataracts within a few days of birth, hypoglycemia, galactosemia, galactosuria, hepatosplenomegaly, hypotonia and mental retardation?
Classic Galactosemia is the absence of Gal-1-P uridyl transferase where galactitol accumulates and causes cataracts within a few days of birth, hypoglycemia, galactosemia, galactosuria, hepatosplenomegaly, hypotonia and mental retardation.
What are the absolute contraindications for breastfeeding?
Absolute contraindications for breastfeeding
- Infants with Classic Galactosemia
- Mothers who use illegal drugs
- Mothers infected with HIV, HTLV, active herpes lesion on the breast
- Mothers taking any of the following medications: radioactive isotopes, chemotherapy, and thyrotoxic agents.
Differentiate Gal-1-P uridyl transferase and Galactokinase deficiency.
Both have galactosemia and galactosuria and are managed by eliminating galactose from diet but Classic Galactosemia (Gal-1-P uridyl transferase deficiency) causes cataracts within a few days of birth while galactokinase deficiency causes cataracts later on in early childhood. Classic Galactosemia is also associated with hypoglycemia, hepatosplenomegaly, hypotonia and mental retardation.
Where are disaccharidases and trisaccharidases located?
Disaccharidases and trisaccharidases are located in the intestinal brush border.
What is an important source of fructose?
Dissacharide sucrose in honey and fruits is an important source of fructose.
What are the monosaccharides in sucrose? What is its dietary source? What enzyme hydrolyses it and where?
Sucrose = glucose + fructose (honey and fruits)
hydrolysed by sucrase in the intestinal brush border
Which monosaccharide has the fastest metabolism and greatest yield of energy?
Fructose has the fastest metabolism and greatest yield of energy
What are the 2 important steps in fructose metabolism?
Important steps in fructose metabolism
- Phosphorylation of fructose to F-1-P by hexokinase or fructokinase
- Formation of DHAP and glyceraldehyde from F-1-P by aldolase B
Differentiate Aldolase A from Aldolase B?
Aldolase A is used in glycolysis and uses F-1,6-BP as a substrate while Aldolase B is used in fructose metabolism and uses F-1-P as a substrate.
What enzyme deficiency manifests as appearance of fructose in blood and urine as its only symptom? What enzyme is deficient?
Essential Fructosuria is a defect in fructokinase and is benign and asymptomatic whose only sign is the appearance of fructose in blood and urine.
What enzyme deficiency manifests as hypoglycaemia, jaundice, cirrhosis, and vomiting? What enzyme is deficient? Treatment?
Fructose Intolerance is a deficiency of Aldolase B which manifests as hypoglycaemia, jaundice, cirrhosis, and vomiting. Patient is treated by eliminating of fructose and sucrose from diet.
Differentiate Fructose Intolerance from Essential Fructosuria (enzyme deficiency, symptoms, treatment)
Essential Fructosuria is a defect in fructokinase and is benign and asymptomatic whose only sign is the appearance of fructose in blood and urine.
Fructose Intolerance is a deficiency of Aldolase B which manifests as hypoglycemia, lactic acidosis, jaundice, cirrhosis, and vomiting. Patient is treated by eliminating of fructose and sucrose from diet.
A few days after breast-feeding, an infant developed jaundice and cataracts. The accumulation of what substance is directly responsible for the cataracts?
Galactitol accumulates and causes cataracts within a few days of birth
What is mannose an important component of?
Glycoproteins
What reaction and enzyme catalyses the isomerization of mannose and fructose?
Mannose-6-P → Fructose-6-P in catalyzed by phosphomannose isomerase
What enzyme catalyses glucose → sorbitol? In what organs is it present?
Aldolase reductase catalyses glucose → sorbitol and is found in RBCs, lens, retina, schwann cells, liver, kidney, placenta, ovaries, and seminal vesicles.
What enzyme catalyses sorbitol → fructose? In what organs is it present?
Sorbitol dehydrogenase catalyses sorbitol → fructose and is found only in the seminal vesicles.
Explain the consequence of hyperglycemia in lens and nerves. What disease can this be seen in?
In DM, there is so much glucose that equilibrium favors the formation of sorbitol. Sorbitol cannot cross cell membranes and the lens and nerves lack sorbitol dehydrogenase which leads to intracellular accumulation of sorbitol produces osmotic stresses on cells by drawing water into the insulin-independent tissues. Hydropic lens fibers degenerate and form cataracts. Neuropathy affects all peripheral nerves including pain fibers, motor neurons and the autonomic nervous system.
What is the polyol pathway? Clinical correlate?
In the sorbitol-aldose reductase pathway or polyol pathway, unused glucose is reduced to sorbitol by aldose reductase then sorbitol dehydrogenase can oxidize sorbitol to fructose. Fructose can return to the glycolysis pathway through the action of hexokinase.
The polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves.
What is the pentose phosphate pathway for?
Pentose Phosphate Pathway or Hexose Monophosphate Pathway (HMP shunt) produces important intermediates:
- produces NADPH which provides electrons for
- FA & steroid biosynthesis
- reduction of glutathione
- cytochrome P450
- WBC respiratory burst
- Nitric Oxide synthesis
- Produces ribose-5-P used for synthesis of nucleotides
- Metabolic use of 5-carbon sugars
Where does the pentose phosphate pathway occur? What part of the cell?
The pentose phosphate pathway
- ACTIVE in the liver, adipose, adrenals, thyroid, testes, RBC, lactating mammaries
- LOW in skeletal muscles and non-lactating mammaries.
It occurs in the cytoplasm of the cell.
***active in tissues that produce lipids because NADPH is important in lipid synthesis
What are the substrates and products of the pentose phosphate pathway?
Pentose phosphate pathway
substrate = G-6-P
products = R-5-P, F-6-P, glyceraldehyde-3-P along with NADPH
***No ATP is consumed or produced
What are the 2 phases of the HMP shunt? What are the key enzymes and main products of each?
Phase 1 : Oxidative Phase
key enzyme: G6PD
main products: NADPH, R5P
Phase 2 : Non-Oxidative Phase
key enzyme: transketolases
main products: R5P, F6P, glyceraldehyde-3-P
What can be used to diagnose thiamine deficiency?
RBC transketolase activity can be used to diagnose thiamine deficiency since thiamine is a necessary co-factor of transketolases. Apart from the baseline enzyme activity (which may be normal even in deficiency states), acceleration of enzyme activity after the addition of thiamine pyrophosphate may be diagnostic of thiamine deficiency
True or False:
Transketolase is a specific enzyme.
False. Transketolases is a class of enzymes collectively termed so.
True or False:
Transketolase catalyzes reactions that are irreversible and rate-limiting.
False. Transketolase catalyzes reactions that are reversible and NOT rate-limiting.
What is the most important product of the non-oxidative phase of the PPP? What is used for?
Ribose-5-phosphate is the most important product of the non-oxidative of the PPP and is used for the synthesis of nucleotides.
What is the function of reduced glutathione (G-SH)? Enzymes involved? Co-factors?
Reduced glutathione (G-SH) sequesters harmful H2O2 in a reaction catalysed by glutathione peroxidase with selenium as a co-factor. Oxidized glutathione (GSSG) is returned to its reduced form by glutathione reductase and consumes 1 NADPH in the process.
***only reduced glutathione can remove H2O2
In what cell is the glutathione peroxidase/reductase pathway important?
The glutathione peroxidase/reductase pathway is important in RBCs.
What is the most common disease producing enzyme abnormality in human? It pathogenesis?
G6PD deficiency involves ↓ NADPH in RBCs and ↓ activity of glutathione reductase causing free radicals and peroxides to accumulate. Hemolytic anemia ensues due to poor RBC defense against oxidizing agents.
What are the precipitating factors of hemolytic anemia caused by G6PD deficiency?
The precipitating factors of hemolytic anemia are anything that can cause oxidative stress
- infection - most common
- drugs: Anti-biotics (sulphonamides, chloramphenicol), Anti-malarials (primaquine), Anti-pyretics (except ASA and paracetamol)
- fava beans
What are the findings in G6PD deficiency?
neonatal jaundice 1-4 days after birth
peripheral smear: heinz bodies & bite cells
What is the pathogenesis of the peripheral smear findings of G6PD deficiency?
Altered hemoglobin precipitates within RBCs and form heinz bodies and the presence of which will cause the phagcytic removal by the spleen forming bite cells
What is the pathogenesis of chronic granulomatous disease?
chronic granulomatous disease is deficient in NADPH oxidase which converts oxygen to superoxide in leukocytes (esp neutrophils and MØ ) which are used in the respiratory burst that kills bacteria.
What is the causative agent in severe, persistent and chronic pyogenic infections found in chronic granulomatous disease?
Catalase-positive bacteria:
- All species of Staphylococcus
- Family Enterobacteriaceae (Citrobacter, E.Coli, Enterobacter, Klebsiella, shigella, yersinia, proteus, salmonella, serratia)
- Listeria
- Fungi: Candida & Apergillus
*“CataLASE SPYKES ProteCts Staph, not strep” *
_C_andida, _L_isteria, _A_spergillus, _S_erratia, _E_. Coli
_S_almonella, _P_seudomonas, _Y_esinia, _K_lebsiella, _E_nterobacter,** S**higella
_P_roteus, _C_itrobacter, _Staph_ylococcus
