Heme Metabolism Flashcards
What are the key components of heme?
Porhyrins; made of pyrrole. Contains substituents of acetate, propionate, methyl and vinyl groups
What are the key steps in heme biosynthesis
Step 1 (Commited Step): Succinyl-CoA being turned into ALA via ALA synthase. (2 parts) -occurs in mitochondria Step 2: ALA dehydratase turning ALA into porphobilinogen.
Which enzyme is a target for lead poisoning?
ALA dehydratase
Which reaction requires vitamin B6 as a cofactor?
ALA synthase rxns
What enzyme links 4 porphobilinogens together in a linear fashion?
hydroxymethylbilane synthase
What happens once porphobilinogens are linked?
They form a ring structure in which iron will be placed in the center.
Where is Heme biosynthesis most active?
Liver, Bone marrow and reticulocytes
How is heme synthesis regulated?
Negative feedback inhibition by heme’s action on ALA synthase.
Name the two ways Heme regulates heme synthesis.
Allosteric binding to ALA synthase.
Decreased transcription of ALA synthase via heme binding to the co-repressor of ALA synthase mRNA transcription.
What is porphyria?
An autosomal dominant disorder that arises from genetic mutations of enzymes involved in heme metabolism. Results in accumulatino, and increased excretion of porphoryin.
What happens if there is an enzyme mutation prior to the formation of porphyrinogens?
Accumulations of ALA and PBG; Toxic to nerves and ATPase which could cause paralysis.
What happens if there is an enzyme mutation later in the pathway?
Accumulations of porphyrinogens; Oxidation of these yield photosensitive porphoryins resulting in skin damage.
What are the 3 products of hemoglobin catabolism?
Globin polypeptides, porphyrin ring, ferrous iron
What enzyme degrades hemin?
heme oxygenase
Name the 2 functions of bilirubin
- Can be reoxidized to bliverdin; An antioxidant
2. Can serve as a scavenger for oxidants.
What is non-conjugated bilirubin?
Bilirubin not bonded to anything.
-With limited solubility in aqueous solution. Due to the hydrophobic nature of bilirubin, it must be transported through the blood using the carrier protein, albumin. This bilirubin-albumin complex is then transported to the liver for conjugation.
Can bilirubin be excreted in its hydrophobic form?
No, it must first be converted into a water-soluble product via conjugation in the liver.
1) First glucoronic acid is created from UDP-glucose via UDP-glucose dehydrogenase twice.
2) Glucoronic acid is added to bilirubin via UDP-glucuronosyl-transferase.
3) Next, another glucuronic acid is added via UDP-glucuronosyl-transferase. Now it can be excreted (conjugated).
Once bilirubin is conjugated, how is it excreted?
The intermediate stercobiliogen is excreted in urine; colorless
The other intermediate sterocobilin is excreted in feces; Brown in color
How can serum bilirubin levels be tested?
The vanadate oxidation test; In the presence of NaVO3 (sodium vanadate) at pH 3, bilirubin is oxidized to biliverdin and loses the absorbance at 451 nm. Oxidation occurs with both conjugated and non-conjugated bilirubin. (see coursepack)
How do you calculate the indirect bilirubin (non-conjugate bilirubin)?
Indirect Bilirubin = Total Bilirubin – Direct Bilirubin
What happens when bilirubin can’t be excreted from the body?
Bile pigments are produced, jaundice
Describe neonatal jaundice.
Bilirubin is unconjugated in the neonate because the hepatic system is immature and consequently is unable to filter and secrete bilirubin. Therefore, excess bilirubin accumulates in the blood, a condition known as hyperbilirbinemia.
Which enzymes can cause hyperbilirubinemia
UDP-gluconyl transferase and UDP-gluconyl dehydrogenase.
What happens when jaundice is not corrected?
The excessive amount of bilirubin may damage developing brain cells leading to learning disabilities or a number of developmental disabilities including vision, hearing, motor movements (kernicterus)
What correlations can be made between types of jaundica and bilirubin levels?
See coursepack
