Poryphin Synthesis, Degradation, Function

Question 1

describe the structure of functional porphyrin

Answer 1

4 pyrrole rings linked by methenyl bridges. conjugated double bonds throughout. metal ion sits in the middle.

roman numerals specify side chain symmetry. type III porphyrins are important in humans and have an asymmetric acetate/propionate side chain switch

Question 2

give some examples of porphyrins

Answer 2

heme- iron
colbalt- cobalamine (vit b12)
chlorophyll- Mg

Question 3

give some examples of heme proteins and what they do

Answer 3

mitochondrial cytochromes- generate H gradient required for ATP synthesis

hemoglobin/myoglobin- oxygen transport

cytochrome p450- metabolism of fat soluble cmpounds (formation of cholesterol and steroid metabolites). responsible for many drug interactions

catalase- antioxidant enzyme that hydrolyzes H2O2

Question 4

cyanide poising

Answer 4

causes irreversible inhibition of mitochondrial cytochrome

Question 5

describe heme biosynthesis

Answer 5

heme is made in the liver and bone marrow

ALA synthase catalyzes rxn of glycine and succinyl CoA to form ALA. This step is irreversible and rate limiting. inhibited by hemin and glucose

ALA dehydrase condenses 2 ALAs to form pyrrole compound PBG

Hydroxymethylbilane synthase condenses 4 molecules of PBG to form Hydroxymethylbilane. this is the second rate limiting step

uroporphyrinogen cosynthase closes the ring to form uroporphyrin I

uroporphyrinogen III cosynthase isomerizes D ring to form uroporphyrinogen III. this is the common precursor.

series of decarboxylation and oxidation rxns convert it to photoporphyrin IX- this glows whereas PBG and porphyrinogens are colorless

ferrochelatase introduces iron to form heme

Question 6

what are the 4 major classes of disease associated w/ heme synthesis?

Answer 6

acute porphyrias, non acute porphyrias, lead poisoning, and iron deficiency anemia

Question 7

describe acute porphyrias

Answer 7

autosomal dominant disorder that produce a blockade in rate limiting steps of heme pathway

Question 8

acute intermittent porphyria

Answer 8

caused by deficiency of hydroxymethylbilane synthase- acute porphyria

symptoms are abdominal pain (increased ALA levels) and neuropsychiatric (ALA is structurally similar to GABA)

triggered by drug ingestion which consume heme, exacerbating the shortage. triggers an increase in ALA synthase and increase in ALA and BPG levels

diagnosed w/ excess PBG in urine, which will turn purple upon standing

treated w/ IV hemin and glucose

Question 9

non acute porphyrias

Answer 9

primarily acquired via diseases associated w/ liver damage

blockade of heme formation occurs beyond hydroxymethylbilane formation, causing abnormal porphyrin derivatives to accumulate in liver and skin

ALA and hydroxymethylbilane synthase levels are normal- no neuro symptoms b/c ALA normal.

Question 10

porphyria cutanea tarda

Answer 10

caused by reduced uroporphyrinogen decarboxylase, which accumulates uroporphyrins

treated w/ regular phlebotomy to remove excess porphyrin metabolites

pts should avoid alcohol and other liver toxins, excess sunlight

Question 11

lead poisining

Answer 11

lead inhibits ALA dehydrase and ferrochelatase

symptoms are same as AIP plus anemia

Question 12

iron-deficiency anemia

Answer 12

translation of eryhtoid ALA synthase mRNA is stimulated by iron in bone marrow. w/ a lack of iron, decrease in heme synthesis, causing anemia.

ALA synthase carries an iron response element, making it susceptible to iron levels

Question 13

describe heme degradation

Answer 13

occurs in liver and spleen

heme is converted to biliverdin (green) by heme oxygenase and NADPH and O2

biliverdin reductase uses NADPH to reduce biliverdin to bilirubin (yellow-red)

albumin carries bilirubin to the liver.

bilirubin glucuronyltransferase conjugates 2 molecules of glucuronic acid to bilirubin to form bilirubin diglucuronide, which is water soluble and secreted in bile

in the intestine, bacteria reduce this to urobilinogen, which is colorless.

this is eventually oxidized to stercobilin, which is brown

some urobilinogen is reabsorbed into blood and transported to the kidney, converted into the yellow urobilin, and secreted

Question 14

jaundice

Answer 14

skin and sclerae turn yellow

hemolytic- red cell lysis leading to increased unconjugated bilirubin

obstructive- blockage of bile ducts- increased conjugated bilirubin

hepatocellular- liver damage causes an increase in liver enzymes AST, ALT

neonatal- low levels of glucuronyltransferase- treated w/ blue flourescent light to catalyze coversion of bilirubin into water soluble metabolites

Question 15

van den bergh rxn

Answer 15

biochemical assay that measures levels of conjugated and unconjugated bilirubin in the blood