Mitsouras lectures Flashcards
Pyruvate Kinase Deficiency
Inherited mutation with autosomal recessive mode of transmission
Decreased ATP production in glycolysis (PK step yields 2 ATP per glucose)
Decrease in ATP production => impaired membrane stability of RBCs => change in cell shape => acanthocytes => cell lysis => nonspherocytic hemolytic anemia
Can be mild to severe depending on severity of mutation (high to low residual enzyme activity)
Mild => no treatment
Severe => spleen enlargement & jaundice require transfusions, splenectomy
Fructokinase deficiency
inability to metabolize fructose
essential fructosuria (benign & asymptomatic)
Fructose accumulates & excreted => can measure in urine
ATP still generated through catabolism of glucose & galactose
Hexokinase (extra-hepatic) metabolism of fructose is intact
Aldolase B deficiency
hereditary fructose intolerance (HFI; severe)
Accumulation of fructose-1-P
in liver
Several clinical signs & disease is severe
Inherited as autosomal recessive
Occurs at frequency of appr. 1:20,000 births
Disease manifestation upon introduction of fructose/sucrose in diet => weaning
Clinical signs => hyperuricemia, hypoglycemia, vomiting & hepatomegaly
Diagnosis by DNA or enzyme testing
Treatment by dietary restriction (removal of fructose, sucrose & sorbitol from diet)
Untreated => liver failure & death
Fructose-1P accumulates & traps Pi => decrease in ATP synthesis (insufficient ATP for gluconeogenesis => inhibition of gluconeogenesis => hypoglycemia with vomiting)
increase in AMP levels (AMP degradation => hyperuricemia)
AMP allosterically inhibits glycogen phosphorylase => inhibition of glycogenolysis => hypoglycemia & hepatomegaly
Galactokinase Deficiency (non-classical galactosemia)
onset upon ingestion of lactose (galactose) => formula or breast milk
inability to metabolize galactose
Galactose accumulates in blood (galactosemia) & urine (galactosuria)
Galactose conversion to galactitol => galactitol accumulation in eye leads to cataracts
GALT Deficiency (Classical Galactosemia)
symptoms: galactosuria, galactosemia, cataracts, liver damage, mental retardation, jaundice, lethargy, hypotonia
mandatory newborn screening- baby looks normal but undiagnosed for short time–>irreversible effects
Accumulation of galactose-1P
in liver (liver damage) &
brain (mental retardation)
Accumulation of galactose
in urine (galactosuria) &
blood (galactosemia)
G6PD Deficiency
low NADPH => low G-SH
Low G-SH => hemolysis
normal functions of G-SH:
- detoxifies free radicals & H2O2
- maintains Cys in Hb & other proteins reduced
- keeps Hb in Fe2+ state
- stabilizes cell membrane
Most common enzyme mutation (400 million worldwide)
X-linked mutation => from carrier mother to affected son
11% of African-American males affected
Also more common in individuals of mediterranean & middle-eastern descent
Heterozygotes are resistant to Plasmodium falciparium malaria
400 + mutations identified => wide spectrum of clinical phenotypes
Severity of symptoms depends on effect of mutation on enzyme activity
Conditions of oxidative stress in RBCs => more G-SH required & if not supplied hemolysis occurs
Oxidative stress => more G-SH required => hemolysis => hemoglobinuria
Neonatal jaundice also observed in deficient individuals
Oxidative stress induced by:
- infections
- fava beans (purine glycoside)
- mothballs
- oxidant drugs
(AAA=antimalarials, antipyretics, antibiotics)
Treat by removing exposure to hemolytic drug
Diagnosis => G6PD enzyme test and/or DNA testing for mutations
DNA test available for newborn screening (NOT part of state NBS programs)
DNA test is for 5 most common US mutations; 90% of population)
Glycosidic bonds of lactose, sucrose, maltose and isomaltose?
Lactose = galactose beta(1-->4) glucose Sucrose = glucose alpha(1-->2) fructose Maltose = glucose alpha(1-->4) glucose Isomaltose = glucose alpha(1-->6) glucose
Polysaccharides and their glycosidic bonds?
Glycogen is a branched animal polysaccharide consisting of glucose α(1,4) glucose bonds in the linear chains and glucose α(1,6) glucose bonds at branchpoints. Starch is a plant polysaccharide consisting of amylose and amylopectin. Amylose is an unbranched polysaccharide with glucose α(1,4) glucose linkages and amylopectin is branched and has the same types of glycosidic linkages as glycogen.
Why is fiber indigestible in humans?
No enzyme in humans to cleave beta(1,4) bonds between glucose in cellulose
alpha-amylase (salivary or pancreatic) cleaves what bond?
glucose alpha (1,4) glucose bonds ONLY Glucose alpha (1,6) glucose are cleaved by brush border disaccharidases
What are the 4 disaccharidases in the SI, what are their substrates, what do they cleave, what are the products?
- Sucrase, sucrose, a(1,2), glucose & fructose
- Isomaltase, isomaltose, a(1,6), glucose
- Maltase, maltose and maltotriose, a(1,4),glucose
- Lactase, lactose, b(1,4), galactose & glucose
Glucose transporters?
- GLUT 1& GLUT3: high affinity/low capacity-brain and RBCs, uptake independent of [blood glc], glc and galactose uptake;
- GLUT2: low affinity/high capacity- liver and pancreas (glc sensors)-large increase in uptake over physiological range, equilibration of [intracellular glc] and [blood glc], glc, glactose and fructose uptake;
- GLUT4: insulin-DEPENDENT glc uptake after meals-skeletal muscle and adipose;
- GLUT5: fructose trabsporter, high affinity;
- GLUT7: membrane of ER in hepatocytes, Glucose transporter; Transports free glucose from ER to cytoplasm for release into blood by GLUT2 (during gluconeogenesis);
- SGLUT1-Na+-dependent, active, requires ATP-in SI and kidney, Glucose, galactose co-transporter with Na+ (same direction); Uptake of sugar from lumen of SI against gradient
Diseases of disaccharide digestion
- Loss of brush border disaccharidases leads to metabolic intolerance, Inability to digest specific disaccharide, Can be due to congenital (inherited; primary) or acquired (secondary) deficiency;
- Congenital deficiency: Due to genetic defect (inherited), Primary deficiency, Permanent effect (irreversible), Early onset (infancy or childhood);
- Acquired deficiency:Due to disease, injury or medication, Secondary deficiency, Transient/ temporary loss of activity (reversible), Adult onset
Lactose intolerance
Lactase deficiency:
1. Congenital: varies by ethnic group, up to 90% of Asian Americans
2) Secondary due to intestinal disease
Symptoms: Lactose digestion followed by: abdominal discomfort, bloating, flatulence & diarrhea
Diagnosis:Lactose tolerance test
1) oral administration 50 g lactose (galactose + glucose)
2) measurement of blood glucose levels every 30 min for 2 hrs
normal > 1.7 mmol/L (30 mg/dL)
deficient < 1.1 mmol/L (20 mg/dL)
Treatment: Limit dietary lactose, Oral lactase administration prior to dairy consumption
Lactic Acidosis
- Lactic acidosis = serum lactate = 4-5 mM and decrease in arterial blood pH.
- Any block in the pathway from pyruvate to AcCoA or TCA cycle or ETC will convert everything back to lactate.
- Conditions resulting in lactic acidosis:
1. Strenuous exercise = anaerobic glycolysis in muscle (muscle cramps)
2. Severe lung disease, high altitude, drowning and CO poisoning = impaired O2 delivery.
3. Cyanide poisoning = blocks oxidative phosphorylation.
4. Alcohol intoxication and Von Gierke’s (GSD) = impaired gluconeogenesis (lactate recycled by Cori cycle/gluconeogenesis)
5. PDH deficiency = blocks pyruvate = AcCoA.
6. α-ketoglutarate dehydrogenase deficiency = blocks TCA
7. Leukemia and metastatic carcinoma = anaerobic glycolysis by tumor cells.
