Biochem: heme synthesis and jaundice part 1

The structure of heme is ____

porphyrins (which are cyclic compounds that bind iron to four pyrrole rings)

Some of the heme proteins, such as ____ have a high turnover rate

hemoglobin (6-7 new hemoglobin/day)

The microsomal CYP monooxygenase is found in the ___ and is responsible for _____

liver; drug metabolism

What are the two major sites of heme biosynthesis? which one produces more?

liver and the erythrocyte-producing cells of the bone marrow (more heme synthesis)

What are the two cellular locations for the steps of heme synthesis? what steps happen at which sites?

cytosol: steps 2-5

mitochondria: steps 1, 6-8

mature red blood cells lack ____, and thus are unable to ____

lack mitochondria (one of the sites of heme synthesis); so they are unable to synthesize heme

What are the starting materials for the synthesis of heme?

glycine and succinyl coA

Which step of heme synthesis is the rate limiting step?

step 1: where glycine and succinyl coA make ALA via ALAS (enzyme)

Step 1 in the synthesis of heme requires what cofactor for decarboxylation?

PLP

Explain the negative feedback regulation for the synthesis of heme

the negative ffedback is going to inhibit the 1st step of heme synthesis (no need to start somehting you aren’t going to finish)

excess heme gets converted to hemin; then the hemin inhibits ALAS1 (the enzyme needed for step 1)

How does hemin inhibit ALAS1 to stop the first step of heme synthesis (neg feedback)?

repressing its transcription, increasing its mRNA degradation, and reducing the import of ALAS to the mitochondria (site of action)

What is the significance of vitamin B6 deficiency?

Vit B6 is a precursor for PLP which is needed for the 1st step in heme synthesis

so deficient B6 → decreased heme synthesis → microcytic sideroblastic anemia

What is the significance of mutations in ALAS2 gene?

ALAS2 is one of the enzymes (ALAS 1 and ALAS2) that can do the 1st step of heme synthesis

recessive disorder leading to deficiency in ALAS2 → X-linked sideroblastic anemia and accumulation of iron (“ringed sideroblasts”)

“ringed sideroblasts” would suggest what?

mutations in the ALAS2 gene

Microcytic, sideroblastic anemia would suggest what?

B6 deficiency

X-linked sideroblastic anemia would suggest what?

mutations in ALAS2 gene

What steps of heme synthesis can be impacted by lead/lead poisoning?

step 2 (replaces the zinc)

step 8 (replaces the iron)

If lead poisoning interferes with step 2 of heme synthesis, what do we expect to see?

accumulation of ALA (made in step 1), impaired heme synthesis, neurological side effects, and ROS production

What is affected and why would we see neurological side effects with lead poisoning?

if lead messes up step 2 of heme synthesis then we get increased ALA

ALA is structurally similar to GABA (neurotransmitter) → neurological side effects

what are the two enzymes and two steps of heme synthesis that are affected by lead/lead poisoning?

step 2: ALA dehydratase

step 8: ferrochelatase

what two things accumulate in the urine with lead poisoning?

ALA and protopophyrin

explain the significance of steps 3 and 4 of heme synthesis? (basic terms)

step 3: the 4 molecules condense

step 4: ring closure

What are porphyrias? (simple explanation)

rare, inherited defects in heme synthesis that causes accumulation and increased excretion of porphyrins or porphyrin precursors

What are two common features of prophyrias as a whole (there are many types)?

decreased heme and increased ALAS1

What are the two porphyrias that occur before step 3? (note the other 5 happen after step 3)

delta-ALA dehydratase porphyria and acute intermittent porphyria