Heme Synthesis & Breakdown - Staudinger Flashcards Preview

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Flashcards in Heme Synthesis & Breakdown - Staudinger Deck (47):
1

How many subunits make up Hemoglobin? How many molecules of iron are present? 5

Four globular sub-units all bound to a single iron

2

Within heme where does iron reside? 5

Found in the center of a porphyrin ring (4) five membered rings

Iron is in its ferrous state --> Fe2+

3

What molecules contain heme? 5

1. Hemoglobin
2. Myoglobin
3. Cytochromes

4

How many heme groups are within one hemoglobin? 6

4

5

What is a pyrrole, how many per heme and how are they connected to one another? 8

Pyrrole --> A five-membered nitrogen containing ring

Heme contains four pyrrole and they are connected by a single carbon

6

Where does heme synthesis occur? 8

Liver and erythroid cell (bone marrow)

7

What are the three phases of heme biosynthesis? 8

Phase I mitochondrial

Phase II Cytostolic

Phase III Mitochondria

8

During phase I (mitochondrial) how is ALA produced? 8

ALA (δ-aminolevulinic acid) is produced from glycine + succinyl coenzyme A (succinyl CoA)

9

Briefly, what happens during phase II (cytostolic) of heme biosynthesis? 8

ALA + ALA = porphobilinogen

4 porphobilinogen = coproporphyringoen III

10

What are porphyrias? 16

Inherited metabolic disorders

11

What causes porphyrias? 8

Defects in one or more stages of heme synthesis

12

What inhibits ALA synthase and is an example of feedback inhibition? 9

Heme and hemin

13

What enzyme adds Fe2+ to heme? 12

Ferrochelatase

14

Differentiate symptoms of acute hepatic versus erythropoietic porphyrias 16

Acute hepatic neurological symptoms

Erythropoietic skin, photosensitivity

15

What kind of Porphyrias is caused by mutation of Porphobilinogen deaminase (PBG)? What is the main feature? 14

Acute intermittent porphyria

Feature --> excessive production of ALA and PBG

16

What kind of Porphyria is caused by mutations of Uroporphyrinogen III Cosynthase? What is the main feature? 14

Congenital erythropoietic porphyria

Feature --> accumulation uroporphyrinogen I

17

What kind of inheritance is associated with congenital erythropoietic porphyria? What are some symptoms? 18

Autosomal recessive (the only porphyria that is!)

symptoms --> Photosensitivity, red color in urine and teeth, anemia

18

What kind of porphyria is caused by mutations of uroporphyrinogen decarboxylase? What is the main feature? 17

Porphyria cutaneous tarda

Feature --> accumulation of uroprophyrinogen III (which eventually converts to uroporphyrinogen I

19

What kind of porphyria is caused by mutations of protoporphyrinogen oxidase? What is the main feature? 17

Variegate porphyria (autosomal dominate)

Feature --> photosensitive & neurologic systems

20

What is the first rate-limiting and highly regulated step of heme synthesis?

ALA Synthase (δ-aminolevulinic acid synthase) – requires B6

21

What activates and inhibits ALA Synthase? 15

(+) vitamin B6

(+) PXR

(-) Heme (feedback inhibition)

(-) hemin (feedback inhibition)

22

What enzymes are involved in phase I of heme synthesis? 15

ALA synthase
ALA dehydratase

23

What enzymes are involved in Phase II of heme synthesis? 15

Porphobilinogen deaminase

Uroporphyrinogen III Cosynthase

24

What enzymes are involved in phase III of heme synthesis? 15

Protoporphyrinogen oxidase

Ferrochelotase

25

What vitamin does ALA Synthase require? 13

pyridoxal phosphate vitamin B6, w/o this patient will have anemia

26

What is a major inhibitor of ALA dehydratase? 9

Lead --> causes anemia

27

What is a major inhibitor of ferrochelatase? 9

Lead --> causes anemia

28

What is a major event of phase 1? 13

Decarboxylation of succinyl CoA

29

Where does break down of red cells occur? 18

In the spleen

30

What is the role of Heme oxigninase? 18

removes the bridge between pyrrole rings of heme

31

PXR regulates the expression of which enzymes? What family are they in? 18

UDP-glucuronyl transferase

UDP Glucoronysl transferase family members

32

What’s the difference between urobilinogen and urobilin? 30

Urobilinogen colorless, found in feces

Urobilin colored, found in urine

33

Where is bilirubin found? 20

in the blood

34

What is the end product of heme oxygenase? 25

Biliverdin

35

What is able to unregulate heme oxygenase 100x? 25

Heme

Metal ions

Phenylhydrazine

36

What does stercobilin do to waste? 30

Gives feces its brown color

37

What causes jaundice? 32

Hyperbilirubinemia

38

In Pre-hepatic jaundice was enzyme is deficient? 34

Glucose 6-phosphate dehydrogenase deficiency

39

What clinical findings characterize pre-hepatic jaundice? 35

Elevated blood levels of unconjugated or indirect billirubin

40

What helps keep bilirubin in solution? 28

Albumin

41

What is the rate-limiting enzyme in the removal of bilirubin from the blood? 28

Bilirubin UDP Glucuronyl transferase

42

What clinical findings characterize intra-hepanic jaundice? 37

Impaired hepatic: uptake, conjugation, or secretion of conjugated billirubin

43

What syndromes are associated with intra-hepatic jaundice? 37

Criggler-Najjar syndrome

Gilbert syndrome

44

What clinical findings characterize post-hepatic jaundice? 40

Eleveated blood levels of conjugated billirubin --> problems with billirubin excretion

AST and ALT levels are normal --> means there must be a blockage

45

What is significant about Gilbert’s syndrome? 42

Of all the genetic errors of billirubin metabolism Gilbert’s syndrome is the only autosomal dominant syndrome

46

What deficiency causes Crigler-Najaf syndrome Type 1? What does it result in?47

Deficiency of UDP-GT

Result severe hyperbilirubinemia

47

What is the clinical finding of Hepatitis? 49

Increased levels of unconjugated and conjugated bilirubin in the blood