Heme Synthesis & Breakdown - Staudinger

Question 1

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

Answer 1

Four globular sub-units all bound to a single iron

Question 2

Within heme where does iron reside? 5

Answer 2

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

Iron is in its ferrous state –> Fe2+

Question 3

What molecules contain heme? 5

Answer 3

1. Hemoglobin
2. Myoglobin
3. Cytochromes

Question 4

How many heme groups are within one hemoglobin? 6

Answer 4

4

Question 5

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

Answer 5

Pyrrole –> A five-membered nitrogen containing ring

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

Question 6

Where does heme synthesis occur? 8

Answer 6

Liver and erythroid cell (bone marrow)

Question 7

What are the three phases of heme biosynthesis? 8

Answer 7

Phase I mitochondrial

Phase II Cytostolic

Phase III Mitochondria

Question 8

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

Answer 8

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

Question 9

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

Answer 9

ALA + ALA = porphobilinogen

4 porphobilinogen = coproporphyringoen III

Question 10

What are porphyrias? 16

Answer 10

Inherited metabolic disorders

Question 11

What causes porphyrias? 8

Answer 11

Defects in one or more stages of heme synthesis

Question 12

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

Answer 12

Heme and hemin

Question 13

What enzyme adds Fe2+ to heme? 12

Answer 13

Ferrochelatase

Question 14

Differentiate symptoms of acute hepatic versus erythropoietic porphyrias 16

Answer 14

Acute hepatic neurological symptoms

Erythropoietic skin, photosensitivity

Question 15

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

Answer 15

Acute intermittent porphyria

Feature –> excessive production of ALA and PBG

Question 16

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

Answer 16

Congenital erythropoietic porphyria

Feature –> accumulation uroporphyrinogen I

Question 17

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

Answer 17

Autosomal recessive (the only porphyria that is!)

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

Question 18

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

Answer 18

Porphyria cutaneous tarda

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

Question 19

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

Answer 19

Variegate porphyria (autosomal dominate)

Feature –> photosensitive & neurologic systems

Question 20

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

Answer 20

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

Question 21

What activates and inhibits ALA Synthase? 15

Answer 21

(+) vitamin B6

(+) PXR

(-) Heme (feedback inhibition)

(-) hemin (feedback inhibition)

Question 22

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

Answer 22

ALA synthase

ALA dehydratase

Question 23

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

Answer 23

Porphobilinogen deaminase

Uroporphyrinogen III Cosynthase

Question 24

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

Answer 24

Protoporphyrinogen oxidase

Ferrochelotase

Question 25

What vitamin does ALA Synthase require? 13

Answer 25

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

Question 26

What is a major inhibitor of ALA dehydratase? 9

Answer 26

Lead --> causes anemia

Question 27

What is a major inhibitor of ferrochelatase? 9

Answer 27

Lead --> causes anemia

Question 28

What is a major event of phase 1? 13

Answer 28

Decarboxylation of succinyl CoA

Question 29

Where does break down of red cells occur? 18

Answer 29

In the spleen

Question 30

What is the role of Heme oxigninase? 18

Answer 30

removes the bridge between pyrrole rings of heme

Question 31

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

Answer 31

UDP-glucuronyl transferase UDP Glucoronysl transferase family members

Question 32

What’s the difference between urobilinogen and urobilin? 30

Answer 32

Urobilinogen colorless, found in feces Urobilin colored, found in urine

Question 33

Where is bilirubin found? 20

Answer 33

in the blood

Question 34

What is the end product of heme oxygenase? 25

Answer 34

Biliverdin

Question 35

What is able to unregulate heme oxygenase 100x? 25

Answer 35

Heme Metal ions Phenylhydrazine

Question 36

What does stercobilin do to waste? 30

Answer 36

Gives feces its brown color

Question 37

What causes jaundice? 32

Answer 37

Hyperbilirubinemia

Question 38

In Pre-hepatic jaundice was enzyme is deficient? 34

Answer 38

Glucose 6-phosphate dehydrogenase deficiency

Question 39

What clinical findings characterize pre-hepatic jaundice? 35

Answer 39

Elevated blood levels of unconjugated or indirect billirubin

Question 40

What helps keep bilirubin in solution? 28

Answer 40

Albumin

Question 41

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

Answer 41

Bilirubin UDP Glucuronyl transferase

Question 42

What clinical findings characterize intra-hepanic jaundice? 37

Answer 42

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

Question 43

What syndromes are associated with intra-hepatic jaundice? 37

Answer 43

Criggler-Najjar syndrome Gilbert syndrome

Question 44

What clinical findings characterize post-hepatic jaundice? 40

Answer 44

Eleveated blood levels of conjugated billirubin --> problems with billirubin excretion AST and ALT levels are normal --> means there must be a blockage

Question 45

What is significant about Gilbert’s syndrome? 42

Answer 45

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

Question 46

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

Answer 46

Deficiency of UDP-GT Result severe hyperbilirubinemia

Question 47

What is the clinical finding of Hepatitis? 49

Answer 47

Increased levels of unconjugated and conjugated bilirubin in the blood