Heme Synthesis And Breakdown

Question 1

Hb is composed of _____ globular subunits, with each bound to an iron containing _________

Answer 1

Four; heme

Question 2

Heme has a heterocyclic __________ ring with _____ present in the center

Answer 2

Porphyrin; Fe2+

[note that iron is present in the ferrous state]

Question 3

Each molecule of heme contains ________ ____-membered rings containing nitrogen connected by single carbon bridges

Answer 3

Four 5-membered rings

Question 4

Heme is present in hemoglobin, ____________, and _________

Answer 4

Myoglobin

Cytochromes

Question 5

Heme synthesis primarily occurs in the __________ and erythroid cells of __________ __________

Answer 5

Liver; bone marrow

Question 6

Defects in one or more stages of heme synthesis causes _________

Answer 6

Porphyrias

Question 7

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 ___________

Answer 7

Mitochondria

Cytosol

Mitochondria

Question 8

The final step in heme synthesis is the installation of Fe2+ by _____________

Answer 8

Ferrochelatase

Question 9

What is the rate limiting step of heme synthesis?

Answer 9

Conversion of Glycine + Succinyl CoA –> ALA

Enzyme = ALA synthase + Vitamin B6 cofactor (PLP)

Question 10

What negatively regulates the rate limiting step of heme biosynthesis?

Answer 10

Heme and hemin

Question 11

What disease is associated with a porphobilinogen deaminase deficiency?

Answer 11

Acute intermittent porphyria (hepatic)

Question 12

What disease is associated with uroporphyrinogen II synthase deficiency?

(Inability to get urophorphyrinogen III from hydroxymethylbilane)

Answer 12

Congenital erythropoietic porphyria (erythropoietic)

Question 13

What disease is associated with a uroporphyrinogen decarboxylase deficiency?

Answer 13

Porphyria cutanea tarda (hepatic and erythropoeitic)

this is the most common

Question 14

What results from a deficiency in protoporphyrinogen oxidase?

Answer 14

Variegate porphyria (hepatic derived)

Question 15

What enzyme is responsible for converting protoporphyrin IX into heme in heme biosynthesis, and what acts as an inhibitor at this step?

Answer 15

Ferrochelatase (with the addition of ferrous iron)

Lead inhibits this step

Question 16

____________ are inherited metabolic disorders meaning “purple pigment” and are caused by defects in heme synthesis

Answer 16

Porphyrias

Question 17

There are 2 types of porphyrias, one is acute hepatic, which manifests as _______________ symptoms.

The other type is erythropoietic, which manifests as ____________

Answer 17

Neurological

Photosensitivity

Question 18

Of all the porphyrias, which one is audosomal recessive?

Answer 18

Congenital erythropoietic porphyria (deficiency in uroporphyrinogen III synthase in erythrocytes)

Question 19

Which porphyria is hepatic, autosomal dominant, and results in photosensitivity and neurologic symptoms and developmental delay in children?

Answer 19

Variegate porphyria

Question 20

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

Answer 20

Acute intermittent porphyria

Question 21

King George the III suffered from intermittent episodes of abdominal pain, delirium, hallucinations, and convulsions. What was his diagnosis?

Answer 21

Variegate porphyria

[queen anne and van gogh also had porphyrias]

Question 22

RBCs undergo breakdown every 120 days. What system handles this breakdown?

Answer 22

Reticuloendothelial system, which degrades hemoglobin

Question 23

What are hemoglobins breakdown products?

Answer 23

Globin is broken down into amino acids

Heme is removed for degradation

Question 24

Describe heme breakdown from the point it is released from damaged RBCs

Answer 24

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

Question 25

What enzyme converts heme to biliverdin?

Answer 25

Heme oxygenase

Question 26

What enzyme converts biliverdin to bilirubin?

Answer 26

Biliverdin reductase [NADPH converted to NADP+]

Question 27

Bilirubin is activated when it is conjugated with UDP-GlcA using what enzyme? What conditions are associated with a deficiency in this enzyme?

Answer 27

UDP-glucuronyl transferase Deficiency = Crigler-Najjar syndrome, Gilbert syndrome

Question 28

Urobilin has a _______ color and is excreted in the _______ Stercobilin has a _____ color and is excreted in the _______

Answer 28

Yellow; urine Red-brown; feces

Question 29

The oxidation of heme using heme oxygenase liberates a carbon bridge as ______ and converts iron into the _____ form, producing the ______ pigment in biliverdin

Answer 29

CO; Fe3+; green

Question 30

What process occurs to bilirubin in the small intestine in order to convert it to urobilinogen?

Answer 30

Microbial reduction via gut microbiome bacteria

Question 31

Heme oxygenase is induced 100x by heme, ______ ions, and ______________

Answer 31

Metal; phenylhydrazine

Question 32

What is the rate limiting step in heme breakdown?

Answer 32

Bilirubin conjugation to UDP-GlcA using UDP-GlcA transferase

Question 33

Where does the UDP glucoronate come from that is later conjugated with the bilirubin?

Answer 33

UDP-glucose + 2NAD+ --> UDP-glucoronate using UDP-glucose dehydrogenase

Question 34

Another term for jaundice is ______________, meaning elevated levels of bilirubin in the blood stream

Answer 34

Hyperbilirubinemia [results from an imbalance between production and excretion of bilirubin]

Question 35

What type of jaundice is characterized by an increased production of unconjugated bilirubin, excess hemolysis (hemolytic anemia), and internal hemorrhage?

Answer 35

Pre-hepatic jaundice

Question 36

What enzyme deficiency was given as an example of pre-hepatic jaundice?

Answer 36

Glucose 6 phosphate dehydrogenase

Question 37

Pre-hepatic jaundice clinical findings: Elevated blood levels of ____________ Normal blood levels of ___________ __________ ALT and AST ____________ present in the urine

Answer 37

Unconjugated (indirect BR) Conjugated BR Normal Urobilinogen [direct BR is absent in urine]

Question 38

Criggler-Najjar syndrome and Gillbert syndrome are associated with what type of jaundice?

Answer 38

Intrahepatic

Question 39

Intra-hepatic clinical findings: Variable increases in __________ and __________ _________ in serum ALT and AST Urobilinogen levels in urine ________ __________ detected in urine

Answer 39

Unconjugated BR; conjugated BR Increase Normal Conjugated BR

Question 40

What type of jaundice is characterized by problems with BR excretion and cholestasis (decreased bile flow)?

Answer 40

Post-hepatic jaundice

Question 41

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)

Answer 41

Conjugated; unconjugated Normal

Question 42

Neonatal jaundice is also called ________________

Answer 42

Physiological jaundice

Question 43

What are the 2 major contributing factors to neonatal jaundice?

Answer 43

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

Question 44

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

Answer 44

Phycobilin Soluble [another line of treatment = intra muscular injection of tin-mesoporphyrin which is an inhibitor of heme oxygenase]

Question 45

What syndrome results from a deficiency of UDP-GT due to a complete absence of the gene?

Answer 45

Crigler-Najjar syndrome type I = severe hyperbilirubinemia, BR accumulates in teh brain of babies and causes encephalopathy (kernicturus) and brain damage

Question 46

How is Crigler Najjar (UDP-GT deficiency) treated?

Answer 46

Blood transfusions, phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, liver transplantation

Question 47

What syndrome results from a mutation in the UDP-GT gene, so that the enzyme only has 10% activity?

Answer 47

Crigler Najjar Syndrome type II (benign form)

Question 48

What syndrome is relatively common and results from a reduced activity of UDP-GT (25% activity)?

Answer 48

Gillbert syndrome results in slightly increased serum bilirubin, which may further increase with fasting, stress, or alcohol

Question 49

What is hepatitis?

Answer 49

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

Question 50

Bruise color changes correlate with the sequential breakdown of hemoglobin: Heme = Biliverdin = Bilirubin = Hemosiderin =

Answer 50

``` Heme = red Biliverdin = green Bilirubin = red Hermosiderin = reddish brown ```