Heme Synthesis and Degradation Flashcards
What is the function of the gene ALAS1 and on which chromosome is it located?
It is a ubiquitous/housekeeping gene located on chromosome 3
What is the rate-limiting step in heme synthesis? What are the reactants and product? Where is it produced?
Synthesis of δ-aminolevulinic acid (δ-ALA) from succinyl-CoA and glycine. It is produced in the bone marrow
Which part of the cell do the steps for heme synthesis take place?
The first and last three steps takes place in the mitochondria. The intermediates take place in the cytosol
The accumulation of hydroxymethylbilane and intermediates after leads to what?
The accumulation of hydroxymethylbilane leads to photosensitivity
What enzyme catalyzes the synthesis of δ-aminolevulinic acid (δ-ALA)?
δ-ALA synthase
The synthesis of vitamin B6 and mutations in the ALAS2 gene can cause what?
X-linked sideroblastic anemia
Out of ALAS1 and ALAS2, which is erythroid specific and which one is ubiquitous?
ALAS1 is ubiquitous, ALAS2 is erythroid-specific
Where is ALAS2 expressed?
In which chromosome is it located?
When is it activated and what regulates its activation?
ALAS2 is expressed in RBC precursors. It is located in chromosome X
Expression is induced only during active heme synthesis. Iron availability regulates it, which prevents the accumulation of porphyrin intermediates
What are sideroblasts?
They are abnormal nucleated erythroblasts
What is the treatment for X-linked sideroblastic anemia?
Pyridoxine (vitamin B6), which is a cofactor of ALA-synthase
What is the function of PGC-1α?
It is a coactivator of nuclear receptors and transcription factors, regulates mitochondrial biogenesis and oxidative metabolism.
It induces the synthesis of enzymes involved in FA oxidation and gluconeogenesis. Insulin and glucose inhibit PGC-1α synthesis because of the decreased demand in cytochromes required for the production of ATP in the liver
This disease is due to mutations in ALAD gene
ALAD porphyria
This disease leads to the accumulation of succinylacetone, which is a potent competitive inhibitor of ALAD
Hepatorenal tyrosinemia
This disease leads to anemia and accumulation of δ-ALA
Lead poisoning
What is the action of lead?
It inhibits ALAD activity by displacing zinc atoms from the enzyme
What happens in elevated levels of δ-ALA?
Elevated levels of δ-ALA is neurotoxic that can affect both central and peripheral nerve systems, resulting in memory loss and confusion. It can cause hypertension and hyponatremia via increased production of ADH
How is hydroxymethylbilane (HMB) produced? What catalyzes the reaction?
HMB is produced by condensation of four porphobilinogen molecules
The reaction is catalyzed by PBG-deaminase (PBGD)/HMB synthase
What happens to the final step of the production of protoporphyrin IX? What enhances the reaction?
Introduction of Fe2+. It occurs spontaneously, but very slow. The reaction is enhanced by ferrochelatase
This recessive disease is caused by a deficiency of ALA dehydratase in RBC
ALA dehydratase porphyria
This disease is caused by the gain of function mutation in ALAS2 gene
X-linked dominant protoporphyria
This disease is the most subtype of porphyria. Patients often develop photosensitivity, cutaneous sensitivity is caused by accumulationo f porphyrins under skin, which become phototoxic upon activation by light
Porphyria Cutanea Tardea (PCT)
What are the precipitating factors of porphyria?
Illicit drugs: barbituates, sulfa-containing antibiotics, some antiepileptic drugs, progestogens, and synthetic estrogens
Excessive alcohol consumption, heavy exercise schedule, infections, reproductive hormones, smoking, and severe calorie restriction or fasting
What is the function of haptoglobin?
Hemoglobin-haptoglobin complex is readily metabolized in the liver and spleen forming an iron-globin complex and bilirubin. Prevents loss iron in urine
What is the function of hemopexin?
Binds free heme. The heme-hemopexin complex is taken up by the liver and the iron is stored bound to ferritin
What happens when there is an imbalance between production and excretion of bilirubin?
It results in its increased plasma concentrations (>3 mg/dL) – jaundice
What can cause jaundice?
Jaundice can be caused by an excessive hemolysis is due to trauma or infection. A failure of liver to transport, store, or conjugate bilirubin. Deficiencies of enzymes involved in bilirubin metabolism. Cirrhosis or hepatitis.
What can cause neonatal jaundice?
A combination of two factors: excessive intravascular hemolysis, underdeveloped liver
What can cause prehepatic (hemolytic) jaundice?
This can result from excessive hemolysis (beyond the liver’s ability to conjugate it. Excessive RBC lysis can be a result of — autoimmune disease, hemolytic disease of the newborn, structurally normal RBCs (sickle cell disease). High plasma concentrations of unconjugated bilirubin
Intrahepatic jaundice
Can be caused by impaired uptake, conjugation, or secretion of bilirubin, reflects a general liver (hepatocyte) dysfunction. In this case, hyperbilirubinemia is usually accompanies by other abnormalities in liver function, it can be caused by viruses, toxins, or genetic errors
What can cause posthepatic jaundice? How is it characterized?
Can be caused by an obstruction of the biliary tree. It leads to an increased level of plasma conjugated bilirubin and other biliary metabolites (bile acids). It is characterized by pale colored stools (absence of fecal bilirubin or urobilin). Dark urine is caused by an increased levels of conjugated bilirubin in urine. In a complete obstruction, urobilin is absent from the urine. It can be caused by gallstones or tumors
What is hyperbilirubinemia?
Hyperbilirubinemias are inherited disorders in bilirubin metabolism associated with high plasma levels of unconjugated or conjugated bilirubin
What is the difference between conjugated and unconjugated hyperbilirubinemia?
Unconjugated — insufficient conjugation due to enzyme deficiency, excessive hemolysis
Conjugated hyperbilirubinemia — conjugated bilirubin is more water soluble, conjugated hyperbilirubinemias are less severe in their symptomology than unconjugated
What is the disease that has a relatively mild condition characterized by periods of elevated levels of bilirubin in the blood (hyperbilirubinemia) — episodes are usually caused by dehyration, fasting, or illness, usually is recognized in adolescence but 30% have no symptoms
Gilbert syndrome
What are the differences between Gilbert syndrome’s two inheritance patterns?
It can show two different inheritance patterns — mutations in promoter region — autosomal recessive inheritance while a missense mutation in UGT1A1 gene — autosomal dominant inheritance
What disease is a more severe condition of Gilbert syndrome? How is it treated?
Cringer-Najjar Syndrome
It can be treated with phototherapy (10-12 hrs/day), liver transplant by the age of 5
This disease has an autosomal recessive inheritance — a mutation in both UGT1A1 genes
It is characterized by a complete absence or marked reductionin bilirubin conjugation. A severe unconjugated hyperbilirubinemia that usually presents at birth and affected individuals are at a high risk for kernicterus
Cringer-Najjar Syndrome
What are the similarities between Dubin-Johnson and Rotor syndromes?
Both disorders are characterized by impaired biliary secretion of conjugated bilirubin, there is a presence of conjugated bilirubin in the blood
This disease results from mutations in the ABCC2 gene coding for bile canalicular multispecific organic anion transporter
The transporter is involved in the excretion of many non-bile organic anions by an ATP-requiring process
Lysosomal accumulation of pigment causes the liver to turn black. It is inherited in an autosomal recessive pattern
Dubin-Johnson syndrome
What is the difference between dubbing-johnson syndrome and rotor syndrome?
In the rotor syndrome, the liver cells are not pigmented
This disease is caused by mutations in the SERPINA1 gene that can leads to a shortage (deficiency) of protein and lack of control of neutrophil elastase
Autosomal codominant
10% of infants develop liver disease, jaundice, adults develop liver damage (cirrhosis — swollen abdomen, feet, or legs, and jaundice) due to the formation of scar tissue in the liver
Individuals with A1AD are also at risk of developing a type of liver cancer called hepatocellular carcinoma
Alpha-1 antitrypsin deficiency
What causes the majority of neonatal jaundice and why is it especially dangerous?
lysis of large number of RBCs after birth OR immaturity of the enzymes involved in bilirubin conjugation (UDP-glucuronyltransferase)
High levels of unconjugated bilirubin are toxic to the newborn because it can cross the not fully developed BBB and damage the brain in infants by increased levels of bilirubin
Why is phototherapy effective?
How does it work?
Because phototherapy converts unconjugated bilirubin to a move water-soluble, non-toxic form
A blue light (420-470nm) converts bilirubin into two other compounds called lumirubin and isolumirubin, which are isomers of bilirubin that can be removed from the body without conjugation
What is phenobarbital used for?
Phenopbarbital is often administered to the mother prior to an induced labor of a premature infant. Drug crosses the placenta and induces the synthesis of UDP glucuronyl transferase
