Heme Synthesis & Breakdown - Staudinger Flashcards
How many subunits make up Hemoglobin? How many molecules of iron are present? 5
Four globular sub-units all bound to a single iron
Within heme where does iron reside? 5
Found in the center of a porphyrin ring (4) five membered rings
Iron is in its ferrous state –> Fe2+
What molecules contain heme? 5
- Hemoglobin
- Myoglobin
- Cytochromes
How many heme groups are within one hemoglobin? 6
4
What is a pyrrole, how many per heme and how are they connected to one another? 8
Pyrrole –> A five-membered nitrogen containing ring
Heme contains four pyrrole and they are connected by a single carbon
Where does heme synthesis occur? 8
Liver and erythroid cell (bone marrow)
What are the three phases of heme biosynthesis? 8
Phase I mitochondrial
Phase II Cytostolic
Phase III Mitochondria
During phase I (mitochondrial) how is ALA produced? 8
ALA (δ-aminolevulinic acid) is produced from glycine + succinyl coenzyme A (succinyl CoA)
Briefly, what happens during phase II (cytostolic) of heme biosynthesis? 8
ALA + ALA = porphobilinogen
4 porphobilinogen = coproporphyringoen III
What are porphyrias? 16
Inherited metabolic disorders
What causes porphyrias? 8
Defects in one or more stages of heme synthesis
What inhibits ALA synthase and is an example of feedback inhibition? 9
Heme and hemin
What enzyme adds Fe2+ to heme? 12
Ferrochelatase
Differentiate symptoms of acute hepatic versus erythropoietic porphyrias 16
Acute hepatic neurological symptoms
Erythropoietic skin, photosensitivity
What kind of Porphyrias is caused by mutation of Porphobilinogen deaminase (PBG)? What is the main feature? 14
Acute intermittent porphyria
Feature –> excessive production of ALA and PBG
What kind of Porphyria is caused by mutations of Uroporphyrinogen III Cosynthase? What is the main feature? 14
Congenital erythropoietic porphyria
Feature –> accumulation uroporphyrinogen I
What kind of inheritance is associated with congenital erythropoietic porphyria? What are some symptoms? 18
Autosomal recessive (the only porphyria that is!)
symptoms –> Photosensitivity, red color in urine and teeth, anemia
What kind of porphyria is caused by mutations of uroporphyrinogen decarboxylase? What is the main feature? 17
Porphyria cutaneous tarda
Feature –> accumulation of uroprophyrinogen III (which eventually converts to uroporphyrinogen I
What kind of porphyria is caused by mutations of protoporphyrinogen oxidase? What is the main feature? 17
Variegate porphyria (autosomal dominate)
Feature –> photosensitive & neurologic systems
What is the first rate-limiting and highly regulated step of heme synthesis?
ALA Synthase (δ-aminolevulinic acid synthase) – requires B6
What activates and inhibits ALA Synthase? 15
(+) vitamin B6
(+) PXR
(-) Heme (feedback inhibition)
(-) hemin (feedback inhibition)
What enzymes are involved in phase I of heme synthesis? 15
ALA synthase
ALA dehydratase
What enzymes are involved in Phase II of heme synthesis? 15
Porphobilinogen deaminase
Uroporphyrinogen III Cosynthase
What enzymes are involved in phase III of heme synthesis? 15
Protoporphyrinogen oxidase
Ferrochelotase
What vitamin does ALA Synthase require? 13
pyridoxal phosphate vitamin B6, w/o this patient will have anemia
What is a major inhibitor of ALA dehydratase? 9
Lead –> causes anemia
What is a major inhibitor of ferrochelatase? 9
Lead –> causes anemia
What is a major event of phase 1? 13
Decarboxylation of succinyl CoA
Where does break down of red cells occur? 18
In the spleen
What is the role of Heme oxigninase? 18
removes the bridge between pyrrole rings of heme
PXR regulates the expression of which enzymes? What family are they in? 18
UDP-glucuronyl transferase
UDP Glucoronysl transferase family members
What’s the difference between urobilinogen and urobilin? 30
Urobilinogen colorless, found in feces
Urobilin colored, found in urine
Where is bilirubin found? 20
in the blood
What is the end product of heme oxygenase? 25
Biliverdin
What is able to unregulate heme oxygenase 100x? 25
Heme
Metal ions
Phenylhydrazine
What does stercobilin do to waste? 30
Gives feces its brown color
What causes jaundice? 32
Hyperbilirubinemia
In Pre-hepatic jaundice was enzyme is deficient? 34
Glucose 6-phosphate dehydrogenase deficiency
What clinical findings characterize pre-hepatic jaundice? 35
Elevated blood levels of unconjugated or indirect billirubin
What helps keep bilirubin in solution? 28
Albumin
What is the rate-limiting enzyme in the removal of bilirubin from the blood? 28
Bilirubin UDP Glucuronyl transferase
What clinical findings characterize intra-hepanic jaundice? 37
Impaired hepatic: uptake, conjugation, or secretion of conjugated billirubin
What syndromes are associated with intra-hepatic jaundice? 37
Criggler-Najjar syndrome
Gilbert syndrome
What clinical findings characterize post-hepatic jaundice? 40
Eleveated blood levels of conjugated billirubin –> problems with billirubin excretion
AST and ALT levels are normal –> means there must be a blockage
What is significant about Gilbert’s syndrome? 42
Of all the genetic errors of billirubin metabolism Gilbert’s syndrome is the only autosomal dominant syndrome
What deficiency causes Crigler-Najaf syndrome Type 1? What does it result in?47
Deficiency of UDP-GT
Result severe hyperbilirubinemia
What is the clinical finding of Hepatitis? 49
Increased levels of unconjugated and conjugated bilirubin in the blood
