SYLLABUS 23: Metabolism of Heme

Question 1

function of heme?

Answer 1

cofactor for…

1. oxygen carrier proteins like hemoglobin, myoglobin
2. e- tranfer enzymes like mito cytochromes and cytochrome B5 of microsomes
3. cytochrome P450 drug toxification enzymes
4. catalase
5. prostaglandin synthase
6. tryptophan dixoygenase

and other enzymes

Question 2

where’s heme synthesized

Answer 2

mostly in the livery and erythropoetic tissues like marrow

however all tissues produce heme

Question 3

where does heme synthesis occur

Answer 3

both mito and cyto

Question 4

structure of heme

Answer 4

ring structure, “protoporphyrin IX”

4 pyrrole rings linked by methene bridges

iron in the middle of the ring

Question 5

what is heme synthesized from

Answer 5

succinyl CoA + glycine

succinyl CoA is from valine, methionine, isoleucine, threonine via methylmalonyl mutase-B12 rxn

Question 6

how does heme itself control the synthesis pathway

Answer 6

1. it inhibits translation of ALA mRNA, activity of ALA synthase, and transfer of ALAS into the mito
2. inhibit ferrochetolase

Question 7

what inhibits ferrochetolase

Answer 7

lead

heme, product inhibitor

Question 8

2nd step of heme synthesis?

Answer 8

2 moles of ALA leave mito -> Cyto; there, via ALA dehydratase condense to form Porphobilinogen, PBG, a pyrrole ring structure

Question 9

what is the first step of heme synthesis, where does it occur

Answer 9

in the mito

succinyl CoA from the TCA cycle or from Valine, Isoleucine, Leucine, or Threonine is present

succinyl CoA + glycine -> delta aminolevulinate, ALA via delta aminolevulinic synthase, ALA synthase w/ cofactor PLP-B6

H+ + CO2 + CoA are released in this rxn

rate limiting step

HEME end-product inhibits it

Question 10

overall heme synthesis pathway?

Answer 10

1. in mito, succinyl CoA + glycine -> ALA via ALA synthase, w/ PLP-B6 cofactor; H+ -> CO2 and CoA released
2. ALA -> Cyto

2 moles ALA condense via ALA dehydratase -> 4 PBG

3. 4 PBG via Porphobilogen Deaminase + Uroporphyrinogen Synthase -> Uroporphorinogen III
4. Uroporphorinogen III -> Coproporphorinogen III via Uroporphyrinogen decarboxylase
5. Coproporphorinogen III -> Protoporphyrinogen IX via coproporphyrinogen oxidase
6. Protoporphyrinogen IX -> Mito
7. In mito, Protoporphyrinogen IX -> Protoporphyrin IX via Protoporphyrinogen oxidase

7. Protoporphyrin IX -> HEME via Ferrochetolase which inserts Ferrous (2+) iron into protoporphyrin, producing Heme IX

Question 11

which enzymes of the heme synthesis pathway are sensitive to lead?

Answer 11

1. ALA dehydratase which makes ALA -> PBG
2. Ferrochetolase which makes Protoporphyrin IX -> Heme

Question 12

why is lead poisoning toxic

Answer 12

it inhibits ALA dehydratase and ferrochelatase so inhibits heme synthesis

this causes ALA accumulation -> destroys RBCs -> anemia

Question 13

what is the paint chip issue

Answer 13

old paint had lead as base

children may ingest lead paint chips, and this is toxic

Question 14

difference between heme made in erythropoetic tissue and heme made in liver?

Answer 14

erythropoetic tissue’s heme -> hemoglobin

liver’s heme -> cytochromes, esp Cytochrome P450 enzymes

Question 15

how is Fe toxic

Answer 15

Fe increases ROS

We ingest most Fe; if loose in blood may be destructive to RBC and WBC b/c catalyzes O2 Radical formation

Question 16

how is Fe stored in tissues

Answer 16

in ferritin, a complex of Fe 3+ and apoferritin

Question 17

function of ferritin

Answer 17

powerful antioxidant - it binds Fe, makes Fe stable, doesn’t catalyze O2 radical reactions (i.e. Fenton rxn, Haber-Weiss rxn)

Question 18

in what state is iron absorbed?

in what state is it carried through the body?

Answer 18

absorbed: Ferrous (Fe2+) state
carried: Ferric (3+) state by apotransferrin

Question 19

how is iron usually found in body

Answer 19

bound to proteins, b/c free Iron is toxic

Question 20

what does amount of ferritin in the blood indicate

Answer 20

amount of iron in storage b/c little ferritin is usually present in the blood, but its amount increases as iron stores increase

thus ferritin amount in blood is most sensitive indicator of amount of iron in body’s stores

Question 21

what is hemosiderin

Answer 21

a ferritin complexed w/ additional iron that cannot be readily mobilized

it’s how excess iron absorbed from the diet is stored

Question 22

what happens if there’s a deficiency in a heme biosynthesis pathway enzyme?

Answer 22

accumulation of the porphyrin substrates

causes symptoms and diseases called porphyrias

Question 23

what are important symptoms caused by porphyrias

Answer 23

skin damage, photosensitivity, neurological probelms, GI tract irritation, nausea

Question 24

why do the symptoms of porphyrias occur?

Answer 24

b/c porphyrins accumulate in the skin, intestinal t rack, brain

many have = bonds, and are easily oxidized by singlet O2

Question 25

treatment for porphyrias?

Answer 25

symptomatic treatment

Question 26

lifetime of a RBC?

Answer 26

120 days

Question 27

1/2 life of CYT?

Answer 27

10-20 days

Question 28

what causes heme breakdown?

Answer 28

hemoglobin or CYTP450 enzymes or other enzymes

Question 29

how is heme broken down to bilirubin?

Answer 29

1. heme cleaved by heme oxygenase, a CYP450, to biliverdin

requires O2, NADPH

CO is released

this is mixed funciton oxidase

2. biliverdin is reduced by viliverdin reductase to bilirubin

NADPH is the reductant

3. uncojugated/indirect bilirubin + albumin -> liver
4. in liver, bilirubin is conjugated to glucuronic acid by UDP-Glucuronoyltransferase

produces conjugated/direct bilirubin

4. conjugated bilirubin -> gut, or -> kidney

Question 30

how is bilirubin transported from nonhepatic tissues -> liver

Answer 30

binds to albumin, moves as non-conjugated/indirect bilirubin-albumin complex

goes to liver conjugated to albumin

once in liver, undergoes conjugation

Question 31

what happens to bilirubin once in the liver

Answer 31

conjuating enzymes put a glucose residue as UDP-glucuronate on to the bilirubin; make bilirubin diglucuronide

that -> direct conjugated bilirubin -> bile, -> feces, -> excreted

Question 32

biliverdin reductase fxn?

Answer 32

biliverdin -> bilirubin

uses NADPH

Question 33

function of heme degredation?

Answer 33

recycle hemoglobin of RBCs which have reached end of their lifespan

globin is recycled to amino acids, Fe2+ is recycled, and heme is excreted as bilirubin

Question 34

what gives feces its brown color

Answer 34

breakdown product of bilirubin diglucunoride

Question 35

what gives urine its yellow color

Answer 35

some urobilinogen, an intestinal intermediate, is reabsorbed into blood and excreted as urobilin into urine

uroblinogen gives urine the yellow color

Question 36

cause of jaundice?

Answer 36

accumulation of bilirubin, -> yellowish coloration, bilirubin toxicity, esp to developing brain

Question 37

what metabolically underlies cause of jaundice?

Answer 37

due to hemolysis and RBC breakdown, so bile ducts get blocked

**decreased conjugation enzyes **- usually these develop after the first few days of life; newborns thus are very sensitive to having bilirubin accumulate b/c may not have conjugating enzymes

Question 38

how to treat jaundiced newborn?

Answer 38

put them under blue light radiation which reacts w/ these e- and fragments the bilirubin to small fragments

Question 39

why are aa considered precursors of heme?

Answer 39

4 aa become succinyl CoA - Met, Isol, Thre, Val - and Succinyl CoA + glycine is the first step of heme synthesis pathway

Question 40

why does lead cause anemia?

Answer 40

it inhibits the ALA hydratase and Ferrochelatase steps of heme synthesis

this causes accumulation of ALA

ALA accumulation is toxic -> destroys RBC -> anemia

additionally, insufficient heme + RBC -> insufficient oxygen-carrying-capacity in blood

Question 41

how is heme synthesis regulated

Answer 41

by Heme itself, which end-product inhibits Ferrochetolase
and ALA Synthase, as well as the translation of ALA mRNA, activity of ALA synthase, and transfer of ALAs into the mito.

Question 42

“typical” symptoms associated w/ porphyrias?

Answer 42

skin damaged

photosensitivity

neuro problems

GI tract irritation

nausea

Question 43

reaction catalyzed by heme oxygenase?

Answer 43

heme oxygenase is a CYP450 that catabolizes heme to biliverdin through a mixed function oxidase reaction that uses O2 + NADPH + H+ -> NADP+ + Fe3+ + CO

Question 44

what is oncjugated bilirbin and what function does conjuation provide?

Answer 44

Conjugated bilirubin is bilirubin in the liver that has been conjugated to glucuronic acid by UDP-glucuonoyltransferase; this conjugated, direct bilirubin is soluble, and can be excreted to the bile. This is as opposed to unconjugated bilirubin, which is not soluble in water.