Lect 11 Heme Synthesis & Breakdown Flashcards
Hemoglobin and Heme
What are the features of Porphyrin Rings (Heme)?
What happens with oxidation of iron?
Where is Heme located?
Four 5-membered rings (Pyrroles) with Iron in the center (Ferrous)
Oxidation to Ferric state inactivates Hb
Hb, Myoglobin, Cytochromes
Biosynthesis of Heme
Where does it primarily occur?
What is caused by defects in any stage?
Liver & BM (Erythroid Cells)
Porphyrias
Heme Biosynthesis Phase I: Mitochondria
What is this process? (1 Step)
What enzyme is used?
What cofactor is needed?
Glycine + Succinyl CoA –> ALA
ALA synthase
Vitamin B6 (PLP)
Heme Biosynthesis Phase II: Cytosol
What is this process? (4 Steps)
2 ALA –> Porphobillinogen (PBG) via ALA Dehydratase
PBG –> Hydroxymethylbilane via PBG Deaminase *
Hydroxymethylbilane –> Uroporphyrinogen III via Uroporphyrinogen III Synthase *
Uroporphyrinogen III –> Coproporphyrinogen III via Uroporphyrinogen Decarboxylase *
Heme Biosynthesis Phase III: Mitochondria
What is the process? (3 Steps)
Coproporphyrinogen III –> Protoporphyrinogen IX via Coproporphyrinogen Oxidase *
Protoporphyrinogen IX –> Protoporphyrin IX via Protoporphyrinogen IX Oxidase *
Protoporphyrin IX + Fe2+ –> Heme via Ferrochelatase *
Lead Poisoning
What does lead inactivate in the Heme biosynthesis pathway?
What accumulates?
What does this cause?
What else is impacted?
ALA Dehydratase and Ferrochelatase
ALA and Protoporphyrin IX
Anemia
Energy production due to decreased cytochome synthesis
Porphyrias
What are they caused by?
What are the different types and associated sx?
Defects in heme synthesis
Acute Hepatic (Liver) –> Neurological Sx
Erythropoietic (BM) –> Skin, Photosensitivity
Acute Intermittent Porphyria
What is the defective enzyme?
What type of porphyria?
PBG Deaminase
Hepatic
Congenital Erythropoietic Porphyria
What enzyme is defective?
What type of Porphyria?
What builds up?
What are the Sx?
Uroporphyrinogen III Synthase
Erythropoietic
Uroporphyrinogen I & oxidation product Uroporhyrin I
Red colored urine, Red fluorescence in teeth, Skin photosensitivy
Porphyria Cutanea Tarda (Most Common in US)
What enzyme is defective?
What type of Porphyria?
Uroporphyrinogen Decarboxylase
Hepatoerythropoietic
Variegate Porphyria
What enzyme is defective?
What type of Porphyria?
Protoporphyrinogen IX Oxidase
Hepatic
Heme Degradation
What does Heme oxygenase do and what does it require?
What gets released afterwards?
What happens to Ferrous iron in Heme?
What is the product after Heme and what does it require to be converted into Bilirubin?
Removes connection between pyrrole rings of heme by adding oxygen
Carbon Monoxide (CO)
Oxidized to Ferric iron
Biliverdin requires Biliverdin reductase to form Bilirubin
Conjugation of Bilirubin (BR)
What type of BR is insoluble and bound ot Albumin and where is it taken to?
What happens to BR to make it soluble?
What is conjugation of bilirubin?
Where is it sent afterwards?
Free/Unconjugated/Indirect BR transported to the liver for Hepatic uptake
Conjugated with Glucuronic acid
UDP-Glucuronate and Bilirubin combine using BR UDP glucuronyltransferase to form BR-Diglucuronide (Rate Limiting Step of BR removal)
Releasing into Gall Bladder as Bile
BR in Response to Food
What is BR-Diglucuronide reduced to in the intestines?
Where can that product travel to next?
Urobilinogen
Some reabsorbed by kidneys to produce urobilin (urine)
Some receives further reduction to stercobilin (feces)
Jaundice
Also known as?
What causes this?
What are normal ranges of unconjugated and conjugated BR?
Hyperbilirubinemia
Elevated levels of BR in the blood
Unconjugated: 0.2 -0.9
Conjugated: 0.1 -0.3
Pre-Hepatic Jaundice
What is the cause?
Why would this occur?
Increased production of unconjugated/indirect BR
Excess Hemolysis, Internal Hemorrhage; G6P Dehydrogenase Deficiency (No NADPH)
Intra Hepatic Jaundice
What is the cause?
Associated diseases?
Impaired hepatic uptake, conjugation, or secretion of conjugated BR
Criggler-Najjar Syndrome & Gilbert Syndrome
Post Hepatic Jaundice
Caused by what?
Findings?
Problems with BR excretion
Elevated conjugated BR in blood
Conjugated BR in urine (dark) and no urobilinogen
No urobilinogen in feces (pale stool)
Neonatal Jaundice
Newborns can develop jaundice due to elevated unconjugated BR, what is this called?
What is deficient?
What is being broken down in newborns?
What is the treatment?
Physiological Jaundice
UDP-GT enzyme
Fetal Hb as it is replaced with Adult Hb
Phototherapy
UDP-GT Related Disorders
Crigler-Najjar Syndrome Type I cause and what it leads to?
What can accumulate?
Therapy?
Complete absence of the gene leading to severe hyperbilirubinemia
BR accumulates in brain of babies –> encephalopathy (kernicturus) and brain damage
Blood transfusions; Phototherapy; Heme oxygenase inhibitors; Oral CaPO4 and CO3; Liver Transplant
UDP-GT Related Disorders
Criggler Najjar Syndrome Type II cause?
Gilbert Syndrome cause?
Mutation in UDP-GT gene causing 10% enzyme activity
Reduced activity of UDP-GT (25% activity)
Hepatitis
Causes?
What are the findings?
Where does BR accumulate causing yellow discoloration?
Viral infections (Hep A, B, C); Alocholic Cirrhosis; Liver Cancer
Increased levels of unconjugated and conjugated BR in blood
Skin and Sclera of the eyes
