Heme Synthesis & Breakdown Flashcards
Structure of Hemoglobin (Hb)
Four globular protein sub-units each bound to an iron containing heme.
Describe porphyrin riing structure of heme.
Four 5 membered rings contain nitrogen connected by single carbon bridges.
Iron present in the center in ferrous state.
What is heme present in?
Hb, myoglobin, and cytochromes
Oxidation to ferric state causes what in Hb?
Inactivates it, forms methemoglobin.
Where does biosynthesis of heme occur?
Liver and erythroid cells
Feedback inhibition caused by Heme
delta-ALA synthase
What does lead poisoning inactivate in heme synthesis?
What does this result in.
ALA dehydratase (contains Zn) and ferrochelatase (contains Fe).
Lower energy as cytochromes are not synthesized
Lower heme production
What does Lead Poisoning cause an accumulation of?
What diseases do these result in?
ALA and Protoporphyrin IX
ALA is neurotoxic and resembles neurotransmitter GABA
Neurological disease and Anemea
What are inherited metabolic disorders that casue defects in heme synthesis?
Porphyria
Acute hepatic - neurological symptoms
Erthropoietic- skin, photosensitivity
Porphyria caused by defective PBG deaminase in liver.
What is the name, type, and symptoms?
Acute intermittent porphyria
Hepatic
Neurological dysfunction
Porphyria caused by defective Uroporphyrinogen III synthase (in erythrocytes)
What is the name, type, and symptoms?
Congenital erythropoietic porphyria
Erythroporphyric
Photo sensitivity, red color in urine and teeth
Porphyria caused by defective Uroporphyrinogen decarboxylase.
What is the name, type?
Porphyria cutanea tarda (PCT)
Hepatoerythropoietic
Photosynsitive, wine red urine, bullae on skin of exposed area to sun
MOST COMMON
Porphyria caused by defective Protoporphyrinogen IX oxidase.
What is the name, type, and symptoms?
Variegate porphyria
Hepatic
Famous People - photosentivity and neurological delay development
Congenital erythropoietic porphyria results in the build up of what? What symtops are produced?
Results in build up of uroporphyrinogen I and its oxidation product uroporphyrin I
Produce a red color in urine, red fluorescence in teeth, destruction of rbc, and skin photosensitivity
How does heme degreadation take place?
Reticulo-endothelial system
What are the normal levels of bilirubin in the body?
Unconjugated/indirect/free (0.2-0.9 mg/dl)
Conjugated/direct (0.1-0.3 mg/dl)
What is pre-hepatic jaundice caused by?
Increased production of unconjugated BR
Excess hemolysis (hemolytic anemias)
Internal hemorrhage
Capacity of liver to uptake and/or conjugate and/or
excrete BR exceeded
E.g., glucose-6-PO4 dehydrogenase deficiency
Problems with incompatibility of maternal-fetal blood
groups (in neonates)
Impaired hepatic uptake, conjugation, or secretion of conjugated BR.
Caused by genralized hepatic dysfunction
Intra-hepatic jaundice
Intrahepatic Jaundice findings
Variable increases in unconjugated and conjugated BR depending on the cause (pre- or post-conjugation)
Increase in serum ALT and AST
Conjugated BR detected in urine
Disease examples of Intrahepatic dysfunction
Criggler-Najjar syndrome - defect in Biliruben UDP gluconyltransferase
Gilbert syndrome
Liver cirrhosis
Viral hepatitis
Problems with BR excretion lead to this type of Jaundice.
What are the various names for it?
Post-hepatic Jaundice
AKA Cholestatic jaundice or cholestasis
What can cause Post Hepatic Jaundice
Obstruction to biliary drainage (in liver or bile duct)
Cholangiocarcinoma
Gall stones
Infiltrative liver disease
Lesions (tumor, abscess or granulomatous disease)
Drugs (anabolic hormones, chlorpromazine,
phenytoin)
What are the findings in post-hepatic jaundice
Elevated blood levels of conjugated BR
Conjugated BR is present in urine (dark)
Small increases in unconjugated form
Elevated alkaline phosphatase (ALP)
No urobilinogen in urine
No stercobilin in feces (pale stool)
Neonatal jaundice (physiological jaundice) is caused by a deficiency in what enzyme?
Explain how bilirubin accumulates.
Immature hepatic metabolic pathways
UDP-GT enzyme
The breakdown of fetal hemoglobin to adult hemoglubin causes accumpulation of billirubin
How is physiological jaundice treated?
When exposed to blue flourescent light, bilirubin undergoes photoconversion to form more soluble isomers.
Or inject strong inhibitor of heme oxygenase)
Physiological Jaundice is worrisome why?
Severe hyperbilirubinemia
If it diffuses to basal ganglia it can cause encephalopathy (kernicturus)
What are the 5 therapies for UDP-GT-related disorders?
Blood transfusions
Phototherapy
Heme oxygenase inhibitors
Oral calcium phosphate and carbonate (form complexes with
bilirubin in gut)
Liver transplantation (before brain damage occurs and before phototherapy becomes ineffective)
What is Hepatitis and what are it’s causes?
Inflammation of the liver which may lead to liver dysfunction
Causes – viral infections (Hep A, B, C), alcoholic cirrhosis, liver cancer.
Symptoms of Hepatitis
Increased levels of unconjugated and
conjugated BR in blood
BR accumulates in skin and sclera of the eyes,
causing yellow discoloration
Dark, tea colored urine
What are the two isoforms of ALAS and where are they found?
How are they regulate?
ALAS I (ubiquitous)
ALAS II (only in erythroid cell of bone marrow)
Both regulated by heme and hemin
ALASII has an iron response element which increases it’s transcriiption in the presence of Iron.
What reaction does ALA synthase catalyze?
Where does this occur?
What is the required vitamin?
Gly + Succinyl CoA to Aminovulinic Acid (ALA)
Mitochondria
B6 - Needs PLP
What reaction is catalzed by ALA dehydratase?
Where is this done?
2 ALA to 1 Porphobilinogen (PBG)
Cytosol
What reaction does porphobilinogen deaminase catalyze?
What porphyria can is cause
4 PBG to 1 Hydroxymethylibilane
Acute intermittent porphyria
Enzyme that catalyzes Protophyrin to Heme?
Ferrochelatase
What reaction does Uroporphyrinogen III cosynthase catalyze?
What is the porphyria?
Hydroxymethylbilane to Uroporphrinogen III
Congenital erythropoietic porphyria
Enzyme catalyzes the reaction of uroporphyrinogen III to coproporphyrinogen III.
What porphyria?
Uroporphyrinogen decarboxylase
Porphyria cutanea tarda
What reaction is catalyzed by Uroporphyrinogen decarboxylase?
What is the porphyria?
Uroporphyrinogen III to Coporphyrinogen III
Porphyria Cuteana tarda
What catalyzes the reaction of protophyrinogen IX to protophyrinogen?
What is the porphyria?
Protophyrinogen oxidase
Variegate porphyria
What does heme oxidase produce?
Bilividerin IXa and Fe3+ from Heme
CO2 as well
What reaction does Biliverdin reductase catalyze?
What does it use?
Billiverdin to billirubin
Uses NADPH to make NADP+
What enzyme facilatates the activation of glucose for conjugation of Billiruben?
How does it do so?
UDP glucose dehydrogenase
UDP Glucose + 2NAD+ = UDP-glucuronate + 2NADH + 2H+
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What is the rate limiting step in bilirubin removal from blood?
Biliruben UDP gluconyltransferase
2 UDP-glucouronate + Bilirubin = Bilirubin digluronide
Microcrobes convert Bilirubin-diglucuronide into what?
What does the kidney do after?
What about the intestine?
Bilirubin and then Urobilinogen
Kidney converts to Urobillin (yellow)
Intestine converts to Stercobilin (brown)
BUUS
Results from deficiency of UDP-GT, complete absence of the gene
Crigler-Najjar Syndrome Type 1
Benign form of desease. Results from a mutation in the UDP-GT gene. Enzyme has less activity (10% activity)
Crigler-Najjar Syndrome Type II
Relatively common diease (2-10% of population), results in 25% of regular UDP-GT activity. Serum BR <6mg/dl but may increase with fasting, stress, or alcohol.
Gilbert Syndrome
