120814 heme synthesis

Question 1

major sites of heme synthesis

Answer 1

bone marrow
liver

in virtually all cells EXCEPT mature erythrocytes

Question 2

structure of heme

Answer 2

porphyrin derivative and a single ferrous ion

is called a ferroprotoporphyrin IX (Fe2+ with protoporphyrin IX)

Question 3

hemin

Answer 3

ferriprotoporphyrin IX (contains ferric Fe3+ iron)

Question 4

which steps of heme biosynthesis occur in mitochondria?

Answer 4

1st and last 3 steps

Question 5

step 1 of heme biosynthesis

Answer 5

succinyl coA and glycine make delta aminolevulinate
ALAS catalyzes the rxn

COMMITTED STEP

Question 6

ALAS is what kind of enzyme

Answer 6

pyridoxal phosphate (PLP) dependent enzyme

Question 7

two isoforms of ALAS are

Answer 7

ALAS1-liver
ALAS2-erythroid/reticulocyte

they are regulated DIFFERENTLY

Question 8

how is ALAS2 regulated?

Answer 8

NOT regulated by feedback repression by heme

Question 9

how is ALAS1 regulated?

Answer 9

feedback inhibition by heme or hemin

100 different drugs or metabolites can increase ALAS1 activity

Question 10

step 2 of heme biosynthesis is catalyzed by

Answer 10

ALAD

Question 11

step 2 of heme biosynthesis–the rxn?

Answer 11

two molecules of ALA form one porphobilinogen (PBG)

PBG includes a pyrrole ring

Question 12

ALAD requires what?

Answer 12

zinc

lead and other heavy metals can displace the zinc and eliminate catalytic activity

Question 13

what causes some of the neurological effects of lead poisoning?

Answer 13

high ALA (neurotoxic)

Question 14

step 3 of heme biosyn

Answer 14

porphobilinogen deaminase catalyzes condensation of 4 porphobilinogen molecules to form linear tetrapyrrole (hydroxymethylbilane)

Question 15

uroporphyrinogen III cosynthase’s fxn

Answer 15

tightly associated with PBGD and directs the sterochem of the condensation rxn to yield uroporhyrinogen III isomer which is on the path for heme biosyn

Question 16

step 4 of heme biosyn

Answer 16

uroporphyrinogen decarxylase catalyzes transformation of uroporphyrignoen III to coproporphyrinogen III

Question 17

step 5 of heme biosyn

Answer 17

coproporphyrinogen III is converted to protoporphyrinogen IX by coproporphyrinogen III oxidase (CPO)

Question 18

step 6 of heme biosyn

Answer 18

protoporphyrinogen IX is converted to protoporphyrin IX by protopophyriongen IX oxidase (PPO)

Question 19

step 7 of heme biosyn

Answer 19

Fe2+ is inserted into protoporphyrin IX by ferrochelatase

Question 20

ferrochelatase is inhibited by

Answer 20

lead

Question 21

porphyrias

Answer 21

defect in heme biosynthesis

Question 22

defects early in biosynthetic pathway of heme result in

Answer 22

accumulation of ALA, prophobilinogen

resulting in neurologic dysfxn

Question 23

defects later in biosynthetic pathway of heme result in

Answer 23

accumulation of cyclic tetrapyrroles
resulting in sunlight-induced cutaneous lesions–UV irradiation of cyclic tetrapyrroles generates ROS that can produce cellular damage

Question 24

two distinct porphyria syndromes

Answer 24

acute:
periodic acute attacks

chronic:
derm diseases that may or may not include liver and nervous system

Question 25

what two enzymes are sensitive to lead inhibition?

Answer 25

ferrochelatase
ALA dehydratase (inhibition by lead mimics Doss porphyria)

Question 26

hemoglobin structure

Answer 26

two alpha, two beta

4 heme per hemoglobin tetramer

Question 27

methemoglobin

Answer 27

Fe3+ in an INACTIVE form of hemoglobin

Question 28

allosteric regulation of O2 binding to hemoglobin is mediated by

Answer 28

H+
CO2
DPG
all of the above reduce the affinity for O2

O2-positive regulator

Question 29

H and CO2 are what kind of effectors on affinity of Hb for O2

Answer 29

heterotropic (not O2. O2 would be homotropic)
negative (decrease affinity for O2)
allosteric (bind to site other than the O2 site affected)

Question 30

polymerization of HbS depends on

Answer 30

degree of deoxygenation (deoxygenated HbS forms insoluble polymers)

intracellular hemoglobin concentration

relative amount of HbF present

Question 31

thalassemia

Answer 31

decreased synthesis of adult hemoglobin HbA

Question 32

what happens as a result of beta thalassemia

Answer 32

deficit in HbA

unpaired alpha chains precipitate in RBC precursors resulting in apoptosis

Question 33

beta thalassemia major

Answer 33

two beta thalassemia alleles

Question 34

alpha thalassemia’s effects

Answer 34

less severe than beta thalassemia because unpaired beta chains are more soluble than unpaired alpha chains