Heme Metabolism

Question 1

heme structure

Answer 1

cyclic/porphyrin
central iron ion

Question 2

common heme containing proteins

Answer 2

hemoglobin
myoglobin
cytochromes
enzymes- catalase, peroxidase

involved in electron transport or redox rxns

Question 3

common places for synthesis

Answer 3

bone marrow - RBCs
liver- cytochromes

Question 4

step 1

synthesis pathway

Answer 4

condensation
glycine + succinyl-CoA = 5-ALA
en: 5-ALA synthase w/ vitamin B6
RATE LIMITING

succinyl coA from TCA cycle, @ mitochrondria

Question 5

step 2

synthesis pathway

Answer 5

condensation
2 5-ALA’s > porphobilinogen (PB)
en: ALA dehydratase
inhibited by lead

cytosol

Question 6

step 3

synthesis pathway

Answer 6

4 porphobilinogen (PB) > hydroxymethylbilane
en: PB deaminase

hydroxylme is linear so not photosensitive

Question 7

step 4

synthesis pathway

Answer 7

hydroxymethylbilane > uroporphyrinogen III
en: uroporphyrinogen III synthase

now first cyclic compound so photosensitive

Question 8

step 5

synthesis pathway

Answer 8

decarboxylation
uroporphyrinogen III > coproporphyrinogen III
en: uroporphyrinogen (UP III) decarboxylase
enters mitochondria

Question 9

step 6

synthesis pathway

Answer 9

oxidation
coproporphyrinogen III > protoporphyrinogen IX
protoporphyrinogen IX unstable so readily oxidizes to protoporphyrin IX

Question 10

step 7

synthesis pathway

Answer 10

protoporphyrin IX > heme
en: ferrochelatase
requires Fe2+
inhibited by lead

Question 11

regulation

Answer 11

1. feedback inhibition from heme
2. lead poisoning
3. vitamin B6 deficiency
4. iron deficiency

Question 12

alcohol impact

Answer 12

stimulates hepatic heme synthesis via MEOS

cytochrome P450 synthesis consumes heme = no heme to inhibit ALA synthase

step 1

Question 13

lead poisoning

Answer 13

inhibits ALA dehydratase (2) AND ferrochelatase (6)
accumulate: ALA and protoporphyrin IX @ urine AND serum iron/ferritin

anemia, nausea, neuropathy

ferritin is storage form of Fe2+

Question 14

B6 deficiency

Answer 14

co-factor for ALA synthase (1)
low ALA and protoporphyrin
inc serum iron and ferritin

impact healthy RBCs
sideroblastic anemia

Question 15

iron deficiency

Answer 15

impact heme synthesis
microcytic hypochromic anemia pale and small RBC
low serum iron/ferritin
inc protoporphyrin NORMAL ALA

Question 16

acute intermittent porphyria

biochem features

Answer 16

porphobilinogen (PB) deaminase (3)
acc: ALA and porphobilinogen (PB)

Question 17

acute intermittent porphyria

clinical features

Answer 17

acute episodes abdom pain
neuropathic - paranoia, anxiety, paralysis

latent before puberty

exacerbated by steroids, contraceptives, fasting, and alc

*dark red color urine

more common in women

Question 18

porphyria cutanea tarda

biochem features

Answer 18

uroporphyrinogen decarboxylase (4) mutation
acc: porphyrins (esp uroporphyrin) @ urine
generate ROS bc porphyrins absorb UV light

under UV urine looks pink fluorescent

Question 19

bilirubin

formation

Answer 19

catabolism of heme
majority from breakdown of hemoglobin in RBC

Question 20

heme degradation

Answer 20

1. heme oxygenase cleaves heme ring = biliverdin
2. biliverdin reductase converts it to bilirubin INDIRECT/UNCONJUGATED so water insoluble
3. bilirubin-UGT converts to CONJUGATED/DIRECT so soluble

1. requires oxygen
2. requires NADPH

Question 21

excretion bilirubin

Answer 21

1. old RBC destroyed = hemoglobin released in spleen
2. heme converted to unconjugated bilirubin
3. binds albumin in circulation
4. complex travels to liver
5. gets conjugated w/ glucuronic acid
6. secreted by hepatocytes into biliary canaliculi > thru bile duct into gut
7. gut bacteria convert to urobilinogen
8. spontaneous oxidized to stercobilin >excreted in feces
9. reabsorbed urobilinogen oxidized to urobilin >excreted by kidney

stercobilin gives brown color to feces

Question 22

is bilirubin detectable in urine normally

Answer 22

NOPE

Question 23

jaundice

Answer 23

plasma bilirubin high = hyperbilirubinemia

yellow/orange appearance of skin and white eyes
yelow/red color of urine
acc of unconj in brain (kernicterus) = death

Question 24

jaundice

disease conditions causes

Answer 24

hemolytic crisis/prehepatic
hepatic damage/hepatocellular
bile duct occlusion/posthepatic/cholestatic

Question 25

hemolytic crisis

Answer 25

inc destruction of RBC inc serum bilirubin
-albumin capacity reached
-liver unable to conjugate excess so enters skin and other tissues

cannot be excreted by kidney

Question 26

hemolytic crisis

indications

Answer 26

acc unconjugated serum
feces and urine normal
low hemoglobin

Question 27

causes of prehepatic

Answer 27

G6PDH deficiency = oxidative damage in RBC
sickle cell
Rh factor disease

Question 28

hepatic damage

aka hepatocellular

Answer 28

damaged liver cannot conjugate

Question 29

hepatic damage

indications

Answer 29

acc unconjugated bilirubin in plasma and tissues
pale feces and urine
high serum ALT and AST
kernicterus

Question 30

hepatic damage causes

Answer 30

infections (Hep A, B, C)
liver cirrhosis
alc/drugs
genetics-UGT enzyme deficiency

Crigler Najjar, Gilbert ex of genetic

Question 31

bile duct occlusion/posthepatic

Answer 31

obstruction of biliary duct from
-gallstones
-pancreatic cancer
-biliary cirrhosis
so liver can’t excrete conjugated

Question 32

bile duct occlusion

indicatiosn

Answer 32

conjugated bili excreted by kidney w/ urine
dark orange urine
pale feces bc no bilirubin or urobilin
alkaline phosphatase in serum