Unit III- Heme Synthesis Flashcards
1
Q
Structure of Heme
A
- heme possesses a porphyrin ring, which is constructed from four pyrrole rings
- all heme proteins contain a porphyrin ring structure with iron as the chelated metal
- porphyrins from metal chelates with a variety of metal ions other then just iron- Mg++ (chlorophylls), Zn++ etc
- protoporphrins contain eight side chains that are modified by three different groups: 4 methyl, 2 vinyl, 2 propionate groups
- heme is protoporphyrin IX chelated with iron
2
Q
Different species of heme
A
- Heme a- contains a modification of the number 2 vinyl group
- Heme b contains no modifications
- Heme c covalently bound to cysteine residues of proteins through the two vinyl groups
3
Q
Axial liganding
A
- heme a and b have Histidine on the top and bottom, O2 is bound at the angle
- heme c have Met on one side and His on the other
4
Q
Function of heme
A
- hemoglobin- carry O2 in blood
- myoglobin- store O2 in tissue
- cytochrome C- electron carrier
- catalase- break H2O2
- cytochrome P450- detoxify drugs etc
- Ubiquinol-cytochrome c reductase- electron transport chain
- Cytochrome c oxidase- electron transfer
- Tryptophan pyrrolase- degrade Tryptophan
- Neutrophil NADPH oxidase- makes superoxide to kill bacteria
- NO synthase- makes NO
- cystathionase- enzyme breakdown methyanine
5
Q
Delta-aminolevulinate (ALA) synthesis
A
- enzyme: delta- aminolevulinate synthase (ALAS)
- cofactor: pyridoxal phosphate
- location: mitochondria
- glycine + succinyl CoA —>(lose CO2, CoASH) make delta-aminolevulinate
6
Q
Porphobilinogen synthesis
A
- enzyme: porphobilinogen synthase (ALA dehydrase)
- inhibitor: Lead, contains a Zn cofactor that can be replaced by lead, lead poisoning
- location cytosol
- reaction: a pyrrole ring is synthesized from two molecules of ALA (looks like GABA- accumulation causes many problems of lead poisoning)
7
Q
Uroporphyringoen synthesis
A
- tetrapyrrole synthesized from four molecules of porphobilinogen
- enzyme 1: uroporphyrinogen synthase (PBG deaminase) - catalyses the condensation of four substrate molecules and cyclization to form the tetrapyrolle ring, uroprophyringen I. releases 4 NH3
- enzyme 2: uroporphyrinogen III cosynthase- catalazes isomerization to yield uroprophyrinogen III. The co-enzyme flips the D ring so that the side group orientation is correct
- location- cytosol
8
Q
Protoprophyrin IX synthesis
A
- uroprphyrinogen decarboxylase- catalyzes the decarboxylation of four acetyl side chains of uroporphyrinogen III to methyl groups to form coproporphyrinogen III (located in cytosol)
- coproporhyrinogen oxidase- catalyzes the decarboxylation of two propionyl side chains to vinyl groups to form protoporphyrinogen IX (located in mitochondiral matrix)
- protoprophyrinogen oxidase- removes six hydrogen atoms to form protoporphyin IX (located in mitochondrial matrix)
9
Q
Protoheme IX (heme) synthesis
A
- formed fron protoporphyrin IX by insertion of iron (Fe2+)
- enzyme: Ferrochelatase- also inhibited by lead- competes with iron for insertion
- location: mitochondira
10
Q
Lead inhibition in heme synthesis
A
- blocks both the second and last steps in the pathway
- ALA accumulates and can be found in the serum
- Protoporphyrin IX accumulates, levels do not increase appreciably in the serum due to low solubility
- instead the pathway backs up and increased lvels of coproporphyrinogen III
11
Q
Heme Synthesis Regulation in Erythroid cells
A
- two sites of heme biosynthesis are liver and erythroid cells (85%)
- erythroid cells use heme for hemoglobin; an important function of heme in liver is as the prosthetic group for cytochrome P450 (cytochrome P450s are oxidative enzymes involved in detoxification)
-erythroid cells- synthesize heme at one time in their life and in vast quantities . Heme stimulates the synthesis of enzymes in the heme biosynthetic pathway
12
Q
Heme Synthesis in Liver Cells
A
- liver cells- heme is required in varying amounts throughout a liver cell’s lifetime. Synthesis is tightly controlled
- main target of control in heme biosynthesis is ALA synthase, the enzyme that catalyses the first committed step in heme biosynthesis
- this step is feedback-inhibted by heme through several different pathways
- repression of mRNA synthesis
- inhibition of translation of the ALA synthase mRNA
- inhibition of import of the ALA synthase protein into mitochondria
- direct inhibition of the enzyme
-heme synthesis is induced by toxins or substances that also induce cytochrome P450 synthesis, i.e. acetaminophen, alcohol
13
Q
Porphyrias
A
- genetic deficiencies in heme metabolism. Enzymes are usually partially defective, since a complete deficiency would be lethal. They can occur at every step in the pathway
- Hepatic porphyria- specific for liver synthesis. Hepatic porphryrias come as attacks that are induced by something
- Erythropoietic porphria- specific for erythrocyte heme synthesis. Chronic conditions
- some porphyrias affect both compartments
- most of the symptoms are caused by a build up of biosynthetic precursors
14
Q
Congenital erythropoietic porphyria
A
- deficiency in uroporphyrinogen III co-synthase, enzyme approximately one-third normal concentration, autosomal recessive trait
- accumulation of uroporphyrinogen I and coproporphyrinogen I, anemia, skin is photosensitive such that it ulcerates and forms disfiguring scares, red urine, teeth turn a fluorescent reddish-brown, increased hair growth over entire body
15
Q
Protoporphyria
A
- erythroid cells and less severely in liver
- partial deficiency in ferrochelatase, autosomal dominant
- symptoms similar to, but milder than, congenital erythropoietic porphyria
