Heme synthesis and degradation

Question 1

describe the structure of the heme

Answer 1

poryphyrin 5-membered ring complex N atoms face the Fe2+

Question 2

where is heme synthesized?

Answer 2

liver and erythroid cells of bone marrow

Question 3

what are the three phases of heme synthesis?

Answer 3

1-mitochondria-make ALA from Gly and succinyl CoA
2-cytosol-2ALA combine to PBG, 4 of these make CPP3
3-mitochondria-two oxygenation rxn to install side chain=protoporphyrinogen9 and make conjugated ring, insertion of Fe2+

Question 4

What is ALA?

Answer 4

in mitochondria: delta-aminolevulinic acid (ALA synthase)

Question 5

What is CPP3?

Answer 5

coproporphyrinogen 3-cytosol to mitochondria (uro.. dehydrogenase 3)

Question 6

What is PBG?

Answer 6

porphobilinogen-cytosol (ALA dehydrogenase)

Question 7

Describe ALA synthase

Answer 7

needs B6 (pyridoxal phosphate or PLP)
2 isoforms ALAS1(ubiquitous) and ALAS2 (erythroid cells)
Heme inhibits (feedback)
Iron increases transcription and translation
Decarboxylation rxn

Question 8

What are the 4 most important enzymes to know regarding heme synthesis? Where are they located?

Answer 8

ALA synthase mito
ALA dehydrogenase cyto
Porphobilinogen deaminase cyto
Ferrochelatase mito

Question 9

What enzymes does Pb interact with? What molecules accumulate?

Answer 9

ALA dehydratase
ferrochelatase
ALA and Protoporphyrin IX accumulate

Question 10

What enzymes can have a defect and cause a porphyria?

Answer 10

ALA synthase
porphobilinogen deaminase
uroporphyrinogen 3 cosynthase
uroporphyrinogen decarboxylase
protoporphyrinogen oxidase

Question 11

What type of poryphria would a defect in PBG deaminase (liver) cause?

Answer 11

Acute intermittent hepatic

Question 12

What type of poryphria would a defect in uroporphyrinogen 3 synthase (erythrocytes) cause?

Answer 12

congenital

Question 13

What type of poryphria would a defect in uroporphyrinogen decarboxylase cause?

Answer 13

porphyria cutanea tarda
most common
hepatoerythropoietic

Question 14

What type of poryphria would a defect in protoporphyrinogen IX oxidase cause?

Answer 14

Variegate porphyria

hepatic

Question 15

What phenotype is attributed to a deficiency in uroporphyrinogen 3 synthase?

Answer 15

a build-up of uroporphyrinogen I

red in urine, red flourescence in teeth, skin photosensitivity

Question 16

What enzyme is involved in generating bilirubin from heme?

Answer 16

heme oxygenase cleave the cycle and makes it into a linear form
requires oxygen,

Question 17

Describe biliverdin synthesis

Answer 17

heme oxidase

iron oxidized from ferrous to ferric

Question 18

What is the second eznyme involved in bilirubin synthesis?

Answer 18

biliverdin reductase

eliminates double bond

Question 19

Describe free BR

Answer 19

unconjugated/indirect (insoluble)

bound to albumin

Question 20

Describe direct BR

Answer 20

conjugated with glucoronic acid (soluble)

Question 21

describe conjugation

Answer 21

UDP glucose converted to UDP-glucuronic acid
UDP-glu transferase conjucate free BR and UDPGlu acid
does this twice to add two sugars (X2)

Question 22

What is the rate limiting step of BR removal?

Answer 22

UDP glucuronyl transferase

Question 23

What form is iron in heme? What form does it take after the action of heme oxygenase?

Answer 23

In Hb it is ferrous (Fe2+)

after oxygenase it is ferric (Fe3+)

Question 24

What is the cause of green pigmentation in heme breakdown?

Answer 24

conversion of ferrous to ferric

Fe2+ to Fe3+

Question 25

What carries bilirubin in the blood?

Answer 25

albumin

Question 26

What steps are needed and where in BR excretion?

Answer 26

BR->urobilinogen in intistine urobilinogen taken by kidney->urobilin urobilinogen stays in gut->stercobilin

Question 27

what are characteristics of pre-hepatic jaundice?

Answer 27

hemolytic anemias liver cannot uptake excrete, or conjugate fetal incompatability glucose 6 phosphate dehydrogenase deficiency

Question 28

What are findings of pre-hepatic jaundice?

Answer 28

``` elevated unconjugated BR in blood, normal conjugated levels normal serum levels urobilinogen in urine direct BR not in urine ```

Question 29

What are findings in intra-hepatic jaundice?

Answer 29

unconj and conj BR level=depends increase in serum ALT and AST levels urobilinogen levels in urine is normal conjugated BR in urine

Question 30

Describe characteristics of post-hepatic jaundice

Answer 30

BR cannot be excreted | bile might not flow

Question 31

What are findings in post-hepatic jaundice?

Answer 31

elevated conjugated BR levels in blood normal AST and ALT levels conjugated BR is present in urine (dark)

Question 32

describe neonatal jaundice

Answer 32

elevation of

Question 33

describe neonatal jaundice

Answer 33

``` elevation of un-conjugated BR deficiency of UDP-GT enzyme breakdown of fetal Hb, replaced with adult Hb BR can cause encephalopathy` varies in severity due to causes ```

Question 34

What does phototherapy do?

Answer 34

blue fluorescent light causes BR to convert to more soluble isomers also heme oxygenase inhibitor may be used