Heme Synthesis And Breakdown Flashcards
Hb is composed of _____ globular subunits, with each bound to an iron containing _________
Four; heme
Heme has a heterocyclic __________ ring with _____ present in the center
Porphyrin; Fe2+
[note that iron is present in the ferrous state]
Each molecule of heme contains ________ ____-membered rings containing nitrogen connected by single carbon bridges
Four 5-membered rings
Heme is present in hemoglobin, ____________, and _________
Myoglobin
Cytochromes
Heme synthesis primarily occurs in the __________ and erythroid cells of __________ __________
Liver; bone marrow
Defects in one or more stages of heme synthesis causes _________
Porphyrias
Phase 1 of heme synthesis (synthesis of ALA from Gly and Succinyl CoA) occurs in the ___________
Phase 2 of heme synthesis (condensation of ALAs leading to porphobilinogen and then use of 4 porphobilinogens to assemble the tetrapyrrole ring system) occurs in the ___________
Phase 3 of heme synthesis (several steps to the fully conjugated ring system) occurs in the ___________
Mitochondria
Cytosol
Mitochondria
The final step in heme synthesis is the installation of Fe2+ by _____________
Ferrochelatase
What is the rate limiting step of heme synthesis?
Conversion of Glycine + Succinyl CoA –> ALA
Enzyme = ALA synthase + Vitamin B6 cofactor (PLP)
What negatively regulates the rate limiting step of heme biosynthesis?
Heme and hemin
What disease is associated with a porphobilinogen deaminase deficiency?
Acute intermittent porphyria (hepatic)
What disease is associated with uroporphyrinogen II synthase deficiency?
(Inability to get urophorphyrinogen III from hydroxymethylbilane)
Congenital erythropoietic porphyria (erythropoietic)
What disease is associated with a uroporphyrinogen decarboxylase deficiency?
Porphyria cutanea tarda (hepatic and erythropoeitic)
this is the most common
What results from a deficiency in protoporphyrinogen oxidase?
Variegate porphyria (hepatic derived)
What enzyme is responsible for converting protoporphyrin IX into heme in heme biosynthesis, and what acts as an inhibitor at this step?
Ferrochelatase (with the addition of ferrous iron)
Lead inhibits this step
____________ are inherited metabolic disorders meaning “purple pigment” and are caused by defects in heme synthesis
Porphyrias
There are 2 types of porphyrias, one is acute hepatic, which manifests as _______________ symptoms.
The other type is erythropoietic, which manifests as ____________
Neurological
Photosensitivity
Of all the porphyrias, which one is audosomal recessive?
Congenital erythropoietic porphyria (deficiency in uroporphyrinogen III synthase in erythrocytes)
Which porphyria is hepatic, autosomal dominant, and results in photosensitivity and neurologic symptoms and developmental delay in children?
Variegate porphyria
Which porphyria is hepatic, autosomal dominant, and leads to an excessive production of ALA and PBG, as well as periodic attacks of abdominal pain and neurologic dysfunction
Acute intermittent porphyria
King George the III suffered from intermittent episodes of abdominal pain, delirium, hallucinations, and convulsions. What was his diagnosis?
Variegate porphyria
[queen anne and van gogh also had porphyrias]
RBCs undergo breakdown every 120 days. What system handles this breakdown?
Reticuloendothelial system, which degrades hemoglobin
What are hemoglobins breakdown products?
Globin is broken down into amino acids
Heme is removed for degradation
Describe heme breakdown from the point it is released from damaged RBCs
Heme –> biliverdin –> bilirubin (transferred to liver bound to albumin) –> bilirubin (conjugated to UDP-GlcA x2) –> bilirubin-diglucoronide thru gallbladder to the intestine –> urobilinogen –> urobilin or stercobilin
What enzyme converts heme to biliverdin?
Heme oxygenase
What enzyme converts biliverdin to bilirubin?
Biliverdin reductase
[NADPH converted to NADP+]
Bilirubin is activated when it is conjugated with UDP-GlcA using what enzyme? What conditions are associated with a deficiency in this enzyme?
UDP-glucuronyl transferase
Deficiency = Crigler-Najjar syndrome, Gilbert syndrome
Urobilin has a _______ color and is excreted in the _______
Stercobilin has a _____ color and is excreted in the _______
Yellow; urine
Red-brown; feces
The oxidation of heme using heme oxygenase liberates a carbon bridge as ______ and converts iron into the _____ form, producing the ______ pigment in biliverdin
CO; Fe3+; green
What process occurs to bilirubin in the small intestine in order to convert it to urobilinogen?
Microbial reduction via gut microbiome bacteria
Heme oxygenase is induced 100x by heme, ______ ions, and ______________
Metal; phenylhydrazine
What is the rate limiting step in heme breakdown?
Bilirubin conjugation to UDP-GlcA using UDP-GlcA transferase
Where does the UDP glucoronate come from that is later conjugated with the bilirubin?
UDP-glucose + 2NAD+ –> UDP-glucoronate using UDP-glucose dehydrogenase
Another term for jaundice is ______________, meaning elevated levels of bilirubin in the blood stream
Hyperbilirubinemia
[results from an imbalance between production and excretion of bilirubin]
What type of jaundice is characterized by an increased production of unconjugated bilirubin, excess hemolysis (hemolytic anemia), and internal hemorrhage?
Pre-hepatic jaundice
What enzyme deficiency was given as an example of pre-hepatic jaundice?
Glucose 6 phosphate dehydrogenase
Pre-hepatic jaundice clinical findings:
Elevated blood levels of ____________
Normal blood levels of ___________
__________ ALT and AST
____________ present in the urine
Unconjugated (indirect BR)
Conjugated BR
Normal
Urobilinogen
[direct BR is absent in urine]
Criggler-Najjar syndrome and Gillbert syndrome are associated with what type of jaundice?
Intrahepatic
Intra-hepatic clinical findings:
Variable increases in __________ and __________
_________ in serum ALT and AST
Urobilinogen levels in urine ________
__________ detected in urine
Unconjugated BR; conjugated BR
Increase
Normal
Conjugated BR
What type of jaundice is characterized by problems with BR excretion and cholestasis (decreased bile flow)?
Post-hepatic jaundice
Post-hepatic jaundice clinical findings:
Elevated blood levels of _____________ and small increases of ___________ form
__________ serum AST and ALT
As well as elevated ALP or Alk Phos, elevated bile salts, conjugated BR is present in urine, no urobilinogen in urine, no stercobilin in feces (pale stool)
Conjugated; unconjugated
Normal
Neonatal jaundice is also called ________________
Physiological jaundice
What are the 2 major contributing factors to neonatal jaundice?
Breakdown of fetal Hgb as it is replaced with adult Hgb, and immature hepatic metabolic pathways are unable to conjugate and excrete bilirubin
Deficiency of UDP-GT enzyme
Phototherapy operates on the concept that BR is similar to ___________, a pigment used by certain algae to capture light energy.
When exposed to blue fluorescent light, BR changes conformation to form a more _______ isomer
Phycobilin
Soluble
[another line of treatment = intra muscular injection of tin-mesoporphyrin which is an inhibitor of heme oxygenase]
What syndrome results from a deficiency of UDP-GT due to a complete absence of the gene?
Crigler-Najjar syndrome type I = severe hyperbilirubinemia, BR accumulates in teh brain of babies and causes encephalopathy (kernicturus) and brain damage
How is Crigler Najjar (UDP-GT deficiency) treated?
Blood transfusions, phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, liver transplantation
What syndrome results from a mutation in the UDP-GT gene, so that the enzyme only has 10% activity?
Crigler Najjar Syndrome type II (benign form)
What syndrome is relatively common and results from a reduced activity of UDP-GT (25% activity)?
Gillbert syndrome results in slightly increased serum bilirubin, which may further increase with fasting, stress, or alcohol
What is hepatitis?
Inflammation of the liver, caused by viral infections, cirrhosis, and liver cancer, increased levels of unconjugated and conjugated BR in blood
Results in BR accumulation in skin and sclera of eyes, and dark tea colored urine
Bruise color changes correlate with the sequential breakdown of hemoglobin:
Heme =
Biliverdin =
Bilirubin =
Hemosiderin =
Heme = red Biliverdin = green Bilirubin = red Hermosiderin = reddish brown
