Heme Synthesis and Degradation Flashcards
Hemoprotein functions
Oxygen transport (Hb, Mb)
Drug metabolism, steroid hormone synthesis, and metabolism of unsaturated FAs (eicosanoids)
P450 CYPs
Oxidative phosphorylation (cytochromes):
Succinate dehydrogenase (cytochrome b)
cytochromes b and c1
cytochrome c oxidase
Decomposition of hydrogen peroxide:Peroxidases and Catalase
Heme Synthesis
Location
A majority of heme is produced in a bone marrow (~85%) to form hemoglobin.
High steady-state level of heme synthesis depends on iron availability.
Heme is also produced in hepatocytes and o_ther cells that use cytochromes_ (~15%).
A biosynthesis is turned over rapidly to respond to the changing metabolic requirements.
Heme Synthesis
General Pathway
expression patterns of the enzymes
Synthesized from: Succinyl-CoA and Glycine
2nd, 3rd, and 4th enzymes have genes with dual promotor (erythroid specificity)
tissue-specific expression
The single genes for ALAD, PBGD and URO3S utilize tissue-specific promoters and alternative splicing to generate either identical proteins (ALAD, URO3S) or tissue-specific proteins (PBGD).
5 Processes of heme synthesis
- Formation of the pyrrole.
- Assembly of the tetrapyrrole (porphyrin).
- Modification of the porphyrin side chains.
- Oxidation of protoporphyrinogen IX to protoporphyrin IX .
- Insertion of iron to form a heme.
First rxn of heme synthesis
enzyme
Cofactor
Inhinition
1st reaction is the RLS
g-aminolevulinic acid synthase
pyridoxal phosphate
ALS is inhibited by heme
Location of the reactions
Heme synthesis
First and the last 3: Mitochondria
The remaining rxns: cytoplasm
Photosensitivity
accumulation of intermediates.(starting at hydroxymethylbilane)
ð-Aminolevulenic Acid synthesis
Starting compounds
enzyme (cofactor) & assc deficiency
Condensation of Succinyl-CoA and Glycine. ALA synthase (tissue spc. genes),requires pyridoxal phosphate (B6). Deficiency of vitamin B6 reduces heme synthesis and can cause sideroblastic anemia.
Genes for ALA synthase in humans
Housekeeping ALAS-1 is expressed throughout the body:
chromosome 3.
Its expression changes in response to changed demands for the heme.
Erythroid-specific ALAS-2 is expressed _in RBC precursor_s:
chromosome X.
Expression is induced only during active heme synthesis
ALAS-2 synthesis regulated by iron availability to prevent accumulation of porphyrin intermediates.
Regulation of ALA synthase activity
ALA synthase activity is regulated by the heme:
Heme acts as a negative allosteric regulator
High level of free heme → ALAS heme complex (too big to enter Mt) ► reducing heme synthesis.
Infusion of hematin can abort attacks of porphyria in patients with an inborn error of heme synthesis.
Drugs that are metabolized by Cyt P450 monooxygenase system enhance hepatic ALA synthase activity.
Regulation of ALAS-2 trascription
Transcription of ALAS-2 is controlled by Fe2+-binding element.
Prevents excessive formation of porphyrin intermediates in the absence or low levels of iron.
Hepatic ALA synthase & Cyt P450
Drugs that are metabolized by Cyt P450 monooxygenase system enhance hepatic ALA synthase activity.
An increased requirement for Cyt P450 monooxygenase system need an increased demands for heme and stimulates its synthesis.
Sideroblastic anemia
Sideroblasts are abnormal nucleated erythroblasts.
Mutations in ALAS2 gene is the most common congenital cause
Although it is X-linked disorder, almost half of patient are women because of skewed X-inactivation.
Treated with pyridoxine (cofactor of ALA synthase).
There are no diseases associated with ALAS1 gene mutations.
Most likely due to the importance of the heme for cellular survival.
Effects of fasting or low carb diet on PGC1-a
Glucagon and fasting induce PGC-1α synthesis because of the increased demand in cytochromes required for the production of ATP in the liver necessary for gluconeogenesis.
PGC-1α induces the synthesis of enzymes involved in
- FA oxidation
- Gluconeogenesis
- Heme synthesis (ALAS-1) because of the increased demands in cytochromes required for the production of ATP in the liver.
Insulin and glucose inhibit PGC-1α synthesis because of the decreased demand in cytochromes required for the production of ATP in the liver.
PGC-1a
PGC-1α, a coactivator of nuclear receptors and transcription factors, regulates mitochondrial biogenesis and oxidative metabolism.
It induces the synthesis of the genes invlolved in:
- FA ox
- Gluconeogenesis
- Heme synthesis (ALAS-1)
Synthesis of pyrrole ring
Pyrrole ring is formed by the condensation of two molecules of d-ALA. Catalyzed by d-ALA dehydratase (ALAD)
disorders associated with deficiency of ALAD and elevated levels of ð-ALA
There are three disorders associated with deficiency of ALAD and elevated levels of ð-ALA :
ALAD porphyria is due to mutations in ALAD gene.
Hepatorenal tyrosinemia can lead to the accumulation of succinylacetone, which is a potent competitive inhibitor of ALAD.
Lead poisoning leads to anemia and accumulation of d-ALA.
Lead inhibits ALAD activity by displacing zinc atoms from the enzyme.
The effects of elevated levels of ð-ALA on CNS
Elevated levels of d-ALA can have a neurotoxic affect on both central and peripheral nerve systems.
Memory loss and confusion
The final step of heme synthesis
Final step of heme synthesis is the introduction of Fe2+ into protoporphyrin IX.
Occurs spontaneously, but very slow.
The reaction is enhanced by ferrochelatase.
The enzyme is inhibited by lead (lead poisoning).
Deactivating mutations of ferrochelatase can lead to erythropoetic protoporphyria.
deactivating mutations of ferrochelatase
Deactivating mutations of ferrochelatase can lead to erythropoetic protoporphyria.
ferrochelatase enhances the introduction of Fe<strong>2</strong>+ into protoporphyrin IX.
A potent competetive inhibitor of ALAD
succinylacetone
Hepatorenal tyrosinemia can lead to the accumulation of succinylacetone, which is a potent competitive inhibitor of ALAD.
Lead poisoning and anemia
Lead inhibits ALAD activity (displaces Zn)
Lead poisoning leads to anemia and accumulation of ð-ALA.
Elevated levels of ð-ALA are neurotoxic: memory loss and confusuion
Synthesis of HMB
Hydroxymethylbilane (HMB) is produced by condensation of four porphobilinogen molecules.
Catalyzed by PBG-deaminase also known as HMB-synthase.
This is the first intermediate of heme synthesis pathway an accumulation of which will lead to light sensitivity.
The reaction catalyzed by PBG-deaminase
Hydroxymethylbilane (HMB) is produced by condensation of four porphobilinogen molecules.
PBG-deaminase also known as HMB-synthase.
This is the first intermediate of heme synthesis pathway an accumulation of which will lead to light sensitivity.
the first intermediate of heme synthesis pathway an accumulation of which will lead to light sensitivity
hydroxymethylbilane (HMB)
Iron functions in human
Iron content in human body:
Total 3-4 g (2,5 g in hemoglobin)
~2 g in ferritin complexes that are present in all cells
The main stores are: liver, bone marrow, and spleen.
Functions:
Transport of oxygen
Detoxification through cytochrome P450
Cofactor in iron-containing proteins
Heme iron:
Hemoglobin, myoglobin, cytochrom-c oxidase, and catalase.
Non-heme iron:
Fe-S complexes (xanthine oxidase), DNA synthesis (ribonucleotide reductase)