Flashcards in RR - Carbohydrate Metabolism II Deck (107):
What are the glycogenoses?
AR disorders that increase glycogen synthesis (eg von Gierke's disease) or prevent glycogenolysis (eg Pompe's disease, debranching enzyme deficiencies) and lead to an accumulation of structurally normal or abnormal glycogen within cells.
Glycogenoses - Clinical manifestations depend on which ...?
Tissue (eg muscle, liver, kidney) is affected by glycogen accumulation.
Hypoglycemia occurs only in glycogenoses that interfere with ...?
Gluconeogenesis (eg von Gierke's disease) or liver glycogenolysis (eg deficiency of liver phosphorylase).
Muscle glycogenoses ...?
Like McArdle's disease, do NOT result in hypoglycemia, because muscle uses its glycogen to supply glucose for generation of ATP.
--> Usually produce cramps during exertion.
Galactose and fructose metabolism produces ...?
Regulation of galactose and fructose metabolism?
Neither is regulated.
Genetic deficiencies in enzymes from galactose and fructose lead to ...?
Serious clinical problems such as cataracts and liver damage.
Mention 6 glycogen storage diseases (glycogenoses):
1. von Gierke's (AR).
2. Pompe's (AR).
3. Cori's (AR).
4. Andersen's (AR).
5. McArdle's (AR).
6. Her's (AR).
Von Gierke's - Deficient enzyme?
Glycogen 6-phosphatase (liver and kidney).
Von Gierke's - Glycogen structure:
Von Gierke's - Clinical features:
1. Severe fasting hypoglycemia.
4. Lactic acidosis.
5. Enlarged liver and kidneys (hepatorenomegaly).
Pompe's - Deficient enzyme:
Pompe's - Glycogen structure:
Pompe's - Clinical features (infant form):
1. Mental retardation.
3. Cardiomegaly leading to DEATH by age 2.
Pompe's - Clinical features (adult form):
Gradual skeletal myopathy.
Cori's - Deficient enzyme:
Debranching enzyme (muscle and liver), amylo-α-1,6-glucosidase.
Cori's - Glycogen structure:
Abnormal: Many short-branched chains (alpha-limit dextrins).
Cori's - Clinical features:
1. Mild hypoglycemia.
--> Decrease in free glucose after epinephrine challenge.
Andersen's - Deficient enzyme:
Branching enzyme (liver and spleen), glucosyl 4,6-transferase.
Andersen's - Glycogen structure:
Few long chains with very few branches.
Andersen's - Clinical features:
3. Liver failure leading to DEATH by age 2.
McArdle's - Deficient enzyme:
Muscle glycogen phosphorylase.
McArdle's - Glycogen storage:
McArdle's - Clinical features:
1. Muscle CRAMPING.
3. Myoglobinuria with strenuous exercise.
4. No increase in lactic acid after exercise.
Hers' - Deficient enzyme:
Liver glycogen phosphorylase.
Hers' - Glycogen structure:
Hers' - Clinical features:
Similar to von Gierke's disease but less severe.
Galactose metabolism - Galactose undergoes an exchange reaction with ...?
UDP-glucose to produce glucose 1-P and UDP-galactose, using the rate-limiting enzyme GALT (galactose 1-phosphate uridyltransferase).
UDP-galactose provides galactose units for ...?
Lactose synthesis in breast tissue (epimerase reaction) and synthesis of glycoproteins, glycolipids, and glycosaminoglycans in other tissues.
Galactose metabolism - The net output of the pathway is ...?
Galactose metabolism - Interface with other pathways:
If galactose accumulates in other tissues containing ALDOSE REDUCTASE (eg lens, neural tissue), it is converted into a sugar alcohol (polyol) called GALACTICOL, which is osmotically active.
Which is the rate-limiting enzyme in fructose metabolism?
Aldolase B is primarily located in the ...?
Liver and, to a lesser extent, in the small intestine and proximal renal tubules.
Aldolase B converts ...?
Fructose 1-P into the 3-carbon intermediates (trioses) DHAP and glyceraldehyde.
Because fructose metabolism bypasses PFK, it can be rapidly ...?
Converted into acetyl CoA and into fat.
Fructokinase, like galactokinase, is found primarily in the ...?
Fructokinase does what?
It phosphorylates fructose at the first carbon (C1) position instead of the (C6) position.
--> Aldolase B can cleave both forms of fructose phosphate.
Fructose metabolism - Interface with other pathways:
Fructose is a precursor for amino sugars in glycoproteins and glycolipids.
Pentose phosphate pathway - The oxidative brach:
Consists of 3 IRREVERSIBLE reactions that convert glucose 6-P to ribulose 5-P with the release of CO2 + formation of NADPH.
Pentose phosphate pathway - The non oxidative branch:
Consists of a series of REVERSIBLE reactions that interconvert various sugars that produce ribose 5-P + intermediates used in glycolysis and gluconeogenesis.
Increased activity of the pentose phosphate pathway occurs in tissues that ...?
Consume NADPH in reductive biosynthetic pathways.
Ribose 5-P is used for ...?
RNA and DNA synthesis.
NADPH is used for ...?
Reductive biosynthesis and for maintaining GSH in the reduced state.
Pentose phosphate pathway - Oxidative branch - Rate-limiting enzyme?
G6PD --> Converts glucose 6-P to 6-phosphogluconolactone, which is then converted via a series of intermediate reactions to ribulose 5-P.
UDP-glucose can also be converted to ...?
Glucuronic acid - A precursor for conjugation with drugs and toxins in the liver (forms glucuronides).
Pentose phosphate pathway - Non oxidative branch:
Transketolase reactions (thiamine-dependent) are responsible for 2-carbon transfer reactions, while TRANSALDOLASE reactions are involved in 3-carbon transfer reactions.
Transketolase reactions are ... -dependent.
Pentose phosphate pathway - Regulated steps:
Incr. pathway activity occurs in tissues that consumes NADPH in reductive biosynthetic pathways:
1. Adipose tissue for fatty acid synthesis.
2. Gonads and adrenal cortex for steroid hormone synthesis.
3. Liver for fatty acid and cholesterol synthesis.
G6PD is competitively inhibited by its product ...?
The pentose phosphate pathway is also known as ...?
The hexose monophosphate pathway (HMP).
Short, branched oligosaccharides that function in blood group antigens, cell-cell adhesion, and coagulation factors.
Long, linear polysaccharides (glycosaminoglycans) attached to a protein core that function in the ECM.
Glycoproteins - The short, branch-chained oligosaccharides that are attached may be ...?
N- (contain dolichol phosphate) or O-linked.
The A, B, AB, O antigens on RBC surface are produced by which gene?
The H gene.
The H gene occurs in most individuals and codes for a ...?
Glycosyltransferase that attaches fucose to a glycolipid to produce H antigen on RBCs.
Individuals with the A gene:
Codes for an N-acetylgalactosamine transferase that attaches N-acetylgalactosamine to the H antigen --> Produce A antigen.
Individuals with the B gene:
Codes for galactosyltransferase that attaches galactose to the H antigen --> Produce the B antigen.
Individuals with the O gene:
Cannot synthesize transferases, so the surfaces of their RBCs contain only H antigens.
The elderly often lose their ...?
Clinical disorders involving lysosomes - Inclusional (I) cell disease:
It is a rare, inherited condition in which there is a defect in posttranslational modification of lysosomal enzymes in the Golgi.
--> Mannose residues on newly synthesized lysosomal enzymes coming from the RER are NOT phosphorylated because of a deficiency of PHOSPHOTRANSFERASE.
I cell disease - Withouth mannose 6-P to direct the enzymes to lysosomes, ...?
Vesicles that pinch off the Golgi empty the unmarked enzymes into the extracellular space, where they are degraded in the bloodstream.
--> Undigested substrates (eg carbohydrates, lipids, proteins) accumulate as large inclusions in the cytosol.
I cell disease - Symptoms:
Psychomotor retardation and early DEATH.
What is the basis of lysosomal storage diseases?
Deficiencies of degrading enzymes in lysosomes lead to the accumulation of complex substrates in lysosomes.
AR - Deficiency of α-L-iduronidase --> Leads to lysosomal accumulation of DERMATAN SULFATE + HEPARAN SULFATE.
Hurler's disease - Clinical findings:
1. Severe mental retardation.
2. Coarse facial features.
4. Corneal clouding.
5. CAD (ie lipid accumulates in coronary vessels).
6. Vacuoles in the lysosomes of peripheral leukocytes.
X-linked recessive - Deficiency of iduronate sulfatase, leading to lysosomal accumulation of DERMATAN + HEPARAN sulfate.
--> MILDER than Hurler's.
Complexes of UNBRANCHED, acidic polysaccharide chains containing repeating disaccharide units of amino sugars (eg glucosamine or galactosamine) + acid sugars (eg iduronic acid or glucoronic acid).
GAGs other than hyaluronic acid are also ...?
Sulfated GAGs ...?
Attach covalently to a linear core of protein.
GAGs are the major components of ...?
Ground substance in the interstitial tissue and of mucins that compose mucus.
GAGs repeating disaccharide:
Amino sugars and acid sugars.
1. Iduronic acid.
2. Glucuronic acid.
Clinically important GAGs - The largest GAG is ...?
Hyaluronic acid - Features:
1. Binds large amounts of water to form viscous solutions and gels.
2. Major component of synovial fluid (joint lubricant).
3. Glucuronic acid: N-acetylglycosamine repeating disaccharride; only NON sulfated GAG.
Where do we find hyaluronic acid?
1. Vitreous body of the eye.
2. Synovial fluid.
3. Wharton jelly in umbilical cord.
Heparin - Repeating disaccharide:
Glucosamine - Iduronic acid.
Heparan sulfate is located in the ...?
Role of heparan sulfate:
1. Imparts strong negative charge to BM.
2. Repels albumin in the glomerular BM.
Heparan sulfate - Repeating disaccharide:
Glucosamine - glucuronic acid (compare with heparin, glucosamine - iduronic acid).
Only important GAG in CNS:
Heparan sulfate - Integrity of ECM.
The most abundant GAG:
Chondroitin sulfate - Major component of cartilage.
Chondroitin sulfate is lost in ...?
OA - due to digestion of the proteoglycans by MMPs.
Excess chondroitin sulfate and hyaluronic acid in interstitial tissue is called ...?
Myxedema (eg pretibial myxedema in Graves).
Keratan sulfate is found in ...?
Dermatan sulfate is primarily found in ...?
2. Blood vessels.
4. Valvular tissues in the heart.
An increase in dermatan sulfate in heart valves (ie myxomatous degeneration) is associated with ...?
Mitral valve prolapse.
GAGs are degraded in ...?
Summary - Of the 10 reactions in glycolysis ... are reversible.
Summary - Pyruvate kinase regulation:
(+) Fructose 1,6-bisphosphate.
(-) ATP, alanine, glucagon.
Hereditary defects in catabolism of sugars - Glucose and pyruvate metabolism:
1. Pyruvate kinase deficiency (AR, MC enzyme deficiency in the glycolysis).
2. Pyruvate dehydrogenase deficiency (AR).
Hereditary defects in caatbolism of sugars - Galactose metabolism:
1. Galactokinase deficiency (AR).
2. Galactosemia (AR).
Hereditary defects in catabolism of sugars - Fructose metabolism:
1. Essential fructosuria (AR).
2. Hereditary fructose intolerance (AR).
Hereditary defects in catabolism of sugars - Pentose phosphate pathway:
G6PD deficiency. (X-linked R).
Pyruvate kinase deficiency - Metabolic effect:
1. Inadequate ATP for maintaining ion pumps in RBC membrane results in loss of H2O and membrane damage (produces RBCs with spikes).
2. Damaged RBCs, subject to macrophage destruction in the spleen --> UCBemia.
3. Incr. in RBC 2,3-BPG proximal to the enzyme block --> Decr. O2 affinity.
Pyruvate kinase deficiency - Clinical features:
1. Hemolytic anemia + jaundice begin at BIRTH.
2. Anemia is somewhat offset by an increase in 2,3-BPG --> Right shift --> Decr. O2 affinity.
Pyruvate dehydrogenase deficiency - Metabolic effect:
1. Increase in pyruvate with concomitant increase in lactic acid and alanine (by transamination).
2. Decr. in production of acetyl CoA.
3. SEVERE reduction in ATP production.
Pyruvate dehydrogenase deficiency - Clinical features:
1. Lactic acidosis.
2. Neurologic defects.
4. Usually FATAL at early age.
Galactokinase deficiency - Metabolic effect:
Increase in galactose and galacticol (sugar alcohol) --> Cataracts.
Galactosemia - Metabolic effect:
1. Deficiency of GALT.
2. Incr. in galactose (blood, urine).
3. Incr. in galactose 1-P (very toxic).
4. Galacticol (sugar alcohol) --> Osmotically active.
Galactosemia - Clinical features:
2. Mental retardation.
Women with galactosemia can synthesize ...?
LACTOSE in breast milk due to EPIMERASE reaction.
Essential fructosuria - Metabolic effect:
Deficiency of fructokinase - Decr. fructose in blood and urine.
--> Benign condition marked by fructosuria.
Hereditary fructose intolerance - Metabolic effect:
1. Deficiency of aldolase B - Incr. in fructose and fructose 1-P (toxic).
2. Excess fructose traps phosphorus in cells --> Hypophosphatemia - Decr. in ATP, and increase in AMP.
Hereditary fructose intolerance - Clinical features:
1. Toxic liver damage.
2. Renal damage.
3. Severe fasting hypoglycemia.
5. Incr. uric acid level (metabolism of AMP).
G6PD deficiency - Metabolic effect:
Inadequate NADPH production; results in reduction in antioxidant activity of GSH in mature RBCs.