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MCM Final > Heme Synthesis And Breakdown > Flashcards

Heme Synthesis And Breakdown Flashcards

1
Q

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

A

Four; heme

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2
Q

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

A

Porphyrin; Fe2+

[note that iron is present in the ferrous state]

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3
Q

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

A

Four 5-membered rings

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4
Q

Heme is present in hemoglobin, ____________, and _________

A

Myoglobin

Cytochromes

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5
Q

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

A

Liver; bone marrow

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6
Q

Defects in one or more stages of heme synthesis causes _________

A

Porphyrias

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7
Q

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 ___________

A

Mitochondria

Cytosol

Mitochondria

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8
Q

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

A

Ferrochelatase

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9
Q

What is the rate limiting step of heme synthesis?

A

Conversion of Glycine + Succinyl CoA –> ALA

Enzyme = ALA synthase + Vitamin B6 cofactor (PLP)

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10
Q

What negatively regulates the rate limiting step of heme biosynthesis?

A

Heme and hemin

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11
Q

What disease is associated with a porphobilinogen deaminase deficiency?

A

Acute intermittent porphyria (hepatic)

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12
Q

What disease is associated with uroporphyrinogen II synthase deficiency?

(Inability to get urophorphyrinogen III from hydroxymethylbilane)

A

Congenital erythropoietic porphyria (erythropoietic)

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13
Q

What disease is associated with a uroporphyrinogen decarboxylase deficiency?

A

Porphyria cutanea tarda (hepatic and erythropoeitic)

this is the most common

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14
Q

What results from a deficiency in protoporphyrinogen oxidase?

A

Variegate porphyria (hepatic derived)

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15
Q

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

A

Ferrochelatase (with the addition of ferrous iron)

Lead inhibits this step

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16
Q

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

A

Porphyrias

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17
Q

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

The other type is erythropoietic, which manifests as ____________

A

Neurological

Photosensitivity

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18
Q

Of all the porphyrias, which one is audosomal recessive?

A

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

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19
Q

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

A

Variegate porphyria

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20
Q

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

A

Acute intermittent porphyria

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21
Q

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

A

Variegate porphyria

[queen anne and van gogh also had porphyrias]

22
Q

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

A

Reticuloendothelial system, which degrades hemoglobin

23
Q

What are hemoglobins breakdown products?

A

Globin is broken down into amino acids

Heme is removed for degradation

24
Q

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

A

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

25
Q

What enzyme converts heme to biliverdin?

A

Heme oxygenase

26
Q

What enzyme converts biliverdin to bilirubin?

A

Biliverdin reductase

[NADPH converted to NADP+]

27
Q

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

A

UDP-glucuronyl transferase

Deficiency = Crigler-Najjar syndrome, Gilbert syndrome

28
Q

Urobilin has a _______ color and is excreted in the _______

Stercobilin has a _____ color and is excreted in the _______

A

Yellow; urine

Red-brown; feces

29
Q

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

A

CO; Fe3+; green

30
Q

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

A

Microbial reduction via gut microbiome bacteria

31
Q

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

A

Metal; phenylhydrazine

32
Q

What is the rate limiting step in heme breakdown?

A

Bilirubin conjugation to UDP-GlcA using UDP-GlcA transferase

33
Q

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

A

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

34
Q

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

A

Hyperbilirubinemia

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

35
Q

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

A

Pre-hepatic jaundice

36
Q

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

A

Glucose 6 phosphate dehydrogenase

37
Q

Pre-hepatic jaundice clinical findings:

Elevated blood levels of ____________

Normal blood levels of ___________

__________ ALT and AST

____________ present in the urine

A

Unconjugated (indirect BR)

Conjugated BR

Normal

Urobilinogen

[direct BR is absent in urine]

38
Q

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

A

Intrahepatic

39
Q

Intra-hepatic clinical findings:

Variable increases in __________ and __________

_________ in serum ALT and AST

Urobilinogen levels in urine ________

__________ detected in urine

A

Unconjugated BR; conjugated BR

Increase

Normal

Conjugated BR

40
Q

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

A

Post-hepatic jaundice

41
Q

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)

A

Conjugated; unconjugated

Normal

42
Q

Neonatal jaundice is also called ________________

A

Physiological jaundice

43
Q

What are the 2 major contributing factors to neonatal jaundice?

A

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

44
Q

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

A

Phycobilin

Soluble

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

45
Q

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

A

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

46
Q

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

A

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

47
Q

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

A

Crigler Najjar Syndrome type II (benign form)

48
Q

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

A

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

49
Q

What is hepatitis?

A

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

50
Q

Bruise color changes correlate with the sequential breakdown of hemoglobin:

Heme =
Biliverdin =
Bilirubin =
Hemosiderin =

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

MCM Final (14 decks)

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