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MCM-COM 2018 > Heme Synthesis And Breakdown > Flashcards

Heme Synthesis And Breakdown Flashcards

1
Q

Describe the structure of hemoglobin

A

*made of 4 heme

1 heme= 1 porphyrin ring—>4 pyrolle—> 1 ferrous iron

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2
Q

What state is iron in in Hb?

A

Ferrous
2+ state

*oxidation to Fe3+ (ferric) inactivates hb

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3
Q

What structures are heme present in?

A

Hemoglobin
Myoglobin
Cytochromes

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4
Q

They are three phases of heme synthesis, where do they take place?

A

P I and III - mitochondria

P II - cytosol

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5
Q

What parts of the body does most heme synthesis occur

A

Liver and bone marrow

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6
Q

Defect in one or more stages of heme synthesis can cause

A

Porphyrias (lots of porphyrin)

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7
Q

Basic outline of Phase 1 of heme synthesis

A

Reactants:

  1. Glycine
  2. Succinyl co A

Products:
ALA

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8
Q

Basic outline of heme synthesis phase 2

A

2 ALA —> porphobilinogen

4 porphobilinogen—>tetrapyrole ring of coproporphyrinogen III

*MAKES PORPHYRIN RING

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9
Q

Basic outline of heme synthesis stage 4

A

Coproporphyrinogen III—> protoporphyrinogen IX —> protoporphryin IX —> add Fe2+ —> heme

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10
Q

What coenzyme is needed in Phase 1 of heme synthesis for ALA synthase

A

Vitamin B6 (PLP)

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11
Q

Why does B6 deficiency cause anemia

A

Because ALA synthase needs it to make heme

*no heme = anemia

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12
Q

What are the 2 isoforms of ALA

A

ALAS 1 (everywhere)

ALAS 2 (in bone marrow only) 
-has an iron response element in mRNA
  • INHIBITED BY HEME and HEMIN
  • ACTIVATED BY IRON
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13
Q

What activates and inhibits ALA synthase

A

Inhibited by HEME / HEMIN

Activated transcription by IRON

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14
Q

What two enzymes does lead inactivate

A 
ALA dehydratase ( makes PBG)
*has zinc

Ferrochelatase (adds iron)
*has Fe

[accumulation of ALA and protoporphyin IX ]

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15
Q

What three impacts on the body’s healthy does lead poisoning have ?

A
  1. Neurological affects
    (ALA resembles GABA)
  2. Anemia
    (Bc no heme)
  3. Impacts energy production
    (Affects cytochromes heme)
    *fatigue
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16
Q

What is the Greek definition of porphyrias

A

Purple pigment

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17
Q

What is the general defect in porphyria

A

*inherited metabolic disorder

DEFECT IN HEME SYNTHESIS

  • acute hepatic = Neuro problems
  • erythropoietic = photosensitivity
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18
Q

Acute intermittent porphyria is related to what enzyme defect? Where?

A

Porphobilinogen deaminase
(PBG—> hydroxymethybilane)

**HEPATIC

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19
Q

Congenital erythropoietic porphyria is related to what enzyme defect? Where?

A

Uroporphyrinogen III cosynthase
(Hydroxymethylbilane —> uroporphyrinogen III)

  • erythropoietic
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20
Q

porphyria cutaneous Tarda is related to what enzyme defect? Where?

*MOST COMMON IN US

A

Uroporphyrinogen decarboxylase
(Uroporphyrinogen III —> coproporphyrinogen III)

*LIVER AND erythropoietic

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21
Q

Variegate porphyria is related to what enzyme defect? Where?

*celebrites

A

Protoporphryinogen oxidase
(Protophyrinogen IX —> protoporphrin IX)

*HEPATIC

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22
Q

In congenital erythropoietic porphryia, there is a build up of _______ , which oxidizes into _____. This causes what symptoms ?

A

Uroporphyrinogen I

Uroporphyrin I (not a heme intermediate)

  • red urine
  • red teeth
  • skin photosensitivity
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23
Q

What system handles hemoglobin degradation

A

Reticulo-endothelial system

  • globin breaks —> amino acids
  • heme removed for degradation
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24
Q

Heme is broken into biliverdin by what enzyme

A

Heme oxygenase
[needs oxygen]

*porphryrin ring —> tetrapyrrole rings

25
Q

What is released during heme degradation by heme oxygenase

A

Carbon monoxide

26
Q

During heme degradation, what happens to iron

A

Iron IX oxidized

Ferrous—>ferric
2+—> 3+

27
Q

What enzyme converts biliverdin to bilirubin?

A

Biliverdin reductase
-removes double bonds

*uses NADPH

28
Q

What binds to free unconjugated (insoluble) bilirubin when it is first released into the bloodstream?

A

Albumin

29
Q

The bilirubin-albumin complex is made and transported where so that bilirubin can be conjugated

A

The liver

30
Q

In the liver (hepatocytes), bilirubin is conjugated with ________ to make it double

A

Glucuuronic acid

31
Q

UnConjugated/free/indirect bilirubin vs conjugated/direct bilirubin

A

Newly released bilirubin is insoluble and is unconjugated

Bilirubin + glucuronic acid = is soluble and is conjugated

32
Q

What is the general outline of bilirubin conjugation in the liver

A
  1. Glucose is made into UDP-glucouronate

2. UDP-glucuronate + BR conjugated (by BR-UDP glucuronyl transferase) to make BR-monogluconide

33
Q

What is the RLS of bilirubin blood removal

A

BR-monoglucuronide to diuronide

34
Q

Defect in what enezyme of bilirubin conjugation gives rise to many jaundiced

A

Bilirubin-UDP glucuronyltransferase

35
Q

What are the colors associated with heme, biliverdin, and bilirubin

A

Purple

Green

Red-orange

36
Q

Conjugated bilirubin is then sent where to be stored until use ?

A

Stored in the gallbladder as bile

37
Q

Explain what happens to conjugated bilirubin (BR-diglucuronide) after it leaves the gallbladder

A
  1. Converted to free bilirubin
  2. —> urobilinogen
  3. Sent to kidneys (reabsorbed) or sent to colon (not reabsorbed)
38
Q

What happened when urobilinogen is sent to the colon? Kidneys?
And what is the associated colors?

A

Colon:
—> stercobilin —>feces

Kidney:
—>urobilin —> urine

  • urobilnogen is colorless
  • stercobilin is brown
  • urobilin is yellow
39
Q

Jaundice is also known as

A

Hyperbilirubinemia
*elevated blood bilirubin

Imbalance of production and excretion

40
Q

What are the 3 types of Juandice

A
  1. Pre-hepatic
  2. Intracellular-hepatic
  3. Post-hepatic
41
Q

Causes of pre-hepatic juandice

A

*increased unconjugated bilirubin production

(Also: hemolytic anemia’s, hemorrhage, liver cant conjugate bilirubin, G6P dehydrogenase deficiency, imcompability of maternal-fetal blood )

42
Q

What are pre-hepatic jaundice findings

A

*elevated unconjugated bilirubin

  • normal conjugated BR blood levels
  • normal ALT/AST
  • normal urine
43
Q

Causes if intra-hepatic jaundice

A
  • impaired hepatic uptake (faulty transporter)
  • impaired conjugation
  • impaird secretion of conjugated BR

Or hepatic dysfunction from CRIGGLER-NAJJAR SYNDROME or GILBERT SYNDROME

44
Q

Intra-hepatic jaundice findings

A
  • increased ALT/AST
  • conjugated-BR in urine
  • variable direct/indirect BR in blood
  • urobilinogen urine normal
45
Q

What causes post hepatic jaundice (cholestatic jaundice or cholestasis)

A

*problem with indirect bilirubin excretion

From obstruction: gall stones, tumors, drugs,….

46
Q

Post-hepatic jaundice findings

A
  • elevated conjugated BR
    *conjugated BR in urine
    *no urine urobilinogen
    DARK URINE, PALE STOOL

-normal AST/ALT

47
Q

What is the cause of neonatal (physiological) jaundice

A
  • elevated unconjugated BR
  • immature hepatic metabolic pathway cant conjugate
  • UDP-GT enzyme deficiency
48
Q

What is phototherapy?

A
  • treatment for neonatal juandice

- blue fluorescent light makes Bilirubin more soluble

49
Q

Besides phototherapy, what is another way to treat physiological juandice? (Not pathological)

A

-intramuscular injection of tinmesoporphyrin which inhibits heme oxygenase therefore stopping bilirubin production

TINMESOPORPHYRIN INJECTION

50
Q

What are the three UDP-GT related disorders? (Converts indirect bilirubin —>direct)

A

Crigler-Najjar syndrome I

Crigler-Najjar syndrome II

Gilbert syndrome

51
Q
  • complete absence of UDP-GT gene
  • no bilirubin conjugation
  • SEVERE HYPERBILIRUBINEMIA (jaundice)
A

Criggler-Najjar Syndrome Type 1

52
Q

What happens if babies develop Criggler-Najjar syndrome type 1

A
  • indirect bilirubin accumulates in brain

- causes KERNICTURUS encephalopathy and brain damage

53
Q

What are the treatment options for Crigler-Najjar syndrome type 1

A 
Blood transfusion 
Phototherapy 
Heme oxygenase inhibitors 
Oral calcium phosphate/carbonate 
LIVER TRANSPLANT
54
Q

What does oral calcium phosphate/carbonate do in relation to bilirubin

A

Forms a complex with bilirubin in the the gut

55
Q
  • mutation in UDP-GT gene

- decreased activity of conjugated BR formation

A

Criggler-Najjar syndrome type 2

56
Q
  • reduced UDP-GT activity
  • common, benign disorder
  • elevated issues with fasting, stress, or alcohol
A

Gilbert syndrome

57
Q

In hepatitis (liver inflammation) the liver dysfunction (from many different causes) has what affect on bilirubin? Therefore what effect on the body?

A

-increased levels of indirect/direct bilirubin in blood

  • skin and sclera become yellow
  • urine becomes dark
58
Q

Color changes in brushing:

A

Heme(red/purple)—>biliverdin(green) —> bilirubin (orange)—> hemosiderin (brown)

MCM-COM 2018 (14 decks)

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