Heme Flashcards
What is the rate limited step?
What are the other 2 regulated steps?
1) delta-aminolaevulinic acid synthase (ALAS) (inhibited by heme/hemin AND glucose)
2) ALA dehydratase (inhib, by lead)
6) ferrochelatase (inhib. by lead)
Compare and contrast ALAS-1 and ALAS-2, how does globin synthesis compare?
ALAS-1, in all cells, short half life, –activated by steroid hormones in the liver/drugs
-inhibited by hemin/heme and glucose
ALAS-2, in bone marrow, slow response induced by transferrin (IRE, 5’ UTR)
—like globin synthesis:
—–activated by heme conc. and erythropoietin (EPO)
—–Inhibited by low heme conc.- acts as kinase to inhibit translation
What is a porphyria?
Compare and contrast acquired vs. direct.
a misregulated step in heme synthesis leading to lack of heme production and over accumulation of porphyrin
–acquired: inhibition as a result of change in conc. of an inhibitor or cofactor such as Pb, Glycine, B6, or Fe2+
–direct: inhibition due to genetic defect of heme synthesis note symptoms may be intermittent/non-specific: often induced by alcohol, drugs, stress, hormones, or low glucose (extreme dieting)
Compare the 3 direct porphyria examples.
1) Porphyria cutaneous tarda= hepatic, dom inheritance, deficiency in uroporphyrinogen III cosynthase = excess uroporphyrinogen III, +++= photosensitivity/pigmented urine
2) Acute intermittent porphyria: hepatic, auto rec, def. in porphobilinogen deaminase= excess PBG, delta-ALA in urine= abd pain/weakness/CV abnorm/neurologic dysfunction w/ red urine/stool
3) Congenital erythropoietic porphyria: hemolytic anemia lead to extreme photosensitivity/red teeth as a result of urophyrinogen III synthase= excess hydroxymethylbilane
What is jaundice and what are the 3 types?
Jaundice- build up of bilirubin in the blood resulting in deposition on skin/sclera
1) pre-hepatic (hemolysis)
2) hepatic (neonatal, hepatitis, genetic)
3) post-hepatic (bile duct obstruction)
Describe pre-hepatic jaundice
lt in increase in INDIRECT hyperbilirubinemia as Br> liver ability to conjugate, due to increase conjugate in liver= more urobilinogen in blood/urine
often due to severe hemolysis
-sickle cell
-pyruvate kinase deficiency
-G-6-P def.
Describe intrahepatic jaundice.
-impaired uptake, conjugation and/or secretion to bile
–may see indirect and/or direct hyperbilirubinemia depending on duration of issue
—if more conjugated bilirubin=darker in urine
-see increase in liver enzymes (ALT, AST)
—3 genetic causes
+Neonatal jaundice (due to hemolysis at birth and underdeveloped bilirubin glucuronyl transferase if phototherapy is not used to oxidize the bilirubin into a soluble form, it may build up in the basal ganglia leading to toxic encephalopathy- Kernicterus
Describe post-hepatic jaundice
Obstructive jaundice results in increase indirect hyperbilirubinemia
–may increase bile acids in plasma
–increase conjugated bilirubin in urine w/ pale stool w/ decrease urobilinogen
*prolonged obstruction may damage the liver/increase unconjugated bilirubin
What are 3 genetic causes of intrahepatic jaundice?
1) Crigler-najijar syn: very severe deficiency w/ bilirubin glucuronyl transferase w/ type 1 being a total deficiency= huge risk of kernicterus
and type 2 less severe
2) Gilbert synd: common, benign increase of indirect bilirubin due to mutated promoter of bilirubin glucuronyl transferase
3) Dubin-Johnson synd: mild/asymptomatic, mutation w/ MRP2 (multi-drug resistant protein 2) this conjugated bilirubin may not get transported out of liver leading to intermittent jaundice
Compare and contrast haptoglobin and hemopexin.
Haptoglobin: uptakes alpha/beta dimers forming Hb-Hpt complex which are removed by reticulo-endothelial cells and delivered to macrophages
-level of serum haptoglobin reflect hemolysis
Hemopexin- uptake free Heme, methylate then form globin and metheme (Fe3+) –> to
hepatocytes and used for heme oxygenase
