Heme Synthesis Flashcards by Dana E

the enzyme that catalyze the “Rate limiting step” of Heme production is ..

δ-aminoleuvinate synthase

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what do you think will block the rate limiting step of heme synthesis?

Having excess Heme

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Excess Heme blocks …..

“δ-aminoleuvinate synthase”

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If there is increase in heme production, what will happen as form of regulation?

1- Increase Globin Synthesis

2- Inhibits the rate limiting step (δ-aminolevulinate Synthase)

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Excess heme is stored in cells in form of

Hemin

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What is the diffrence btw
Heme
Hemin

Heme= Fe+2 (ferrous)
Hemin= Fe+3 [stored] (ferric)

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Which one ctually the one that inhibits δ-aminolevulinate synthase
Heme= Fe+2
Hemin= Fe+3

Hemin (Fe+3

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CYP450 in liver stimulates Heme synthesis, This means it also stimulates “δ-aminolevulinate synthase

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Why do taking antibiotics (Drugs) increase δ-aminolevulanate synthase activity?

because of CYP450 Activation in the liver

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δ-aminolevulinic acid Dehydrase inhibited by ,,,,

)رصاص( Lead

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What is the importance of Ferrochelatase

it chelates Fe+2 to the heme

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Ferrochelatase is inhibited by…..

Lead

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……condition is related to “δ-aminolevulinate Synthase”

X-linked Sideroblastic Anemia

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What is porphyria?

it is a medical condition in which we have defect in “Heme synthesis” and accumulation of precursors leading to many symptom

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What are the symptoms of Porphyria

1-Photosensitivity
2- Passing Dark urine
3-production of Free radicles

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How can I treat Porphyria?

Simply I give “Heme”
-Bcz Heme will inhibit δ-aminoleuvinate synthase, which will stop the pathway بكل بساطة: راح أوقف التفاعل بالكامل، فما راح تتراكم المكونات ا ساسية

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Why do we give heme if someone has porphyria?

Bcz it inhibits δ-aminolevulinate Synthase

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So what do you think will happen if someone with “Porphyria” took a “drug/antibiotic” that activates “CYP450” activity?

the symptoms will Increase BCZ I’m activating the pathway of heme synthesis, and more Precursors will accumulate,leading to more symptom

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porphyrin is made of

4 pyrole rings

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Each pyrole ring has ….carbons and ….nitrogen

4 carbons and 1 nitrogen

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What type of bond the pyrole ring have

to lower energy of molecule, increase stability, allow for resonance, and give color [red color for rbcs]

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PORPHYRINS composed of four modified pyrrole subunits interconnected at their α carbon atoms via

methine bridges (=CH−).

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What are the diffrence btw uroporphyrin and coproporphyrin

uroporphyrin ; 
-isolated from urine
-has acetate and propionate chains
coproporphyrin ; 
-isolated from feaces r called
-has methyl and propionate chains

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what makes heme useful for mitochondria ?

iron is redox cycling between Fe+2 and Fe+3

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``` ✓ NO synthase ✓ cytochromes ✓ catalase & peroxidase ✓ tryptophan pyrrolase - hemoglobin & myoglobin All of these got ... ```

Heme

In plant chlorophyle the pulory rings chellats to ....

porphyrin being synthesized in mitochondria, then continue in cytosol, then back to mitochondria This case called ?

compartmentalization

compartmentalization for porphyrin is important to allow for tight regulation of heme synthesis. Why?

cuz most of the genes coding for mitochondrial proteins are in the nucleus, the proteins that r made out of the mitochondria should be transported back inside the mitochondria in order to function, and such transport of proteins is used for regulation, i.e.,the protein might be made outside of mitochondria, but if it is not imported to the mitochondria, it is not going to act there,

porhyrin and iron considered as a toxic componant ?

free radicals

Biosynthesis of Heme | the first and the last 3 reactions take place in ..

mitochondria

ALA Synthase regulate

alosterically

ALAS2 contr olled by the availability of

intracellular Fe

ALAS2 GENE found in .... chromosome

X-chromosome

... is the 1st heterocyclic ring formed in the pathway

porphobilinogen

In order to make one porphobilinogen you need ... δ-aminolevulinate

The ....binding sites in mammalian Porphobilinogen Synthase, which include cysteine S ligands, can be occupied by Pb++——> inhibition

Zn++

Inhibition of Porphobilinogen Synthase by Pb++ results in

elevated blood ALA

Inhibition of Porphobilinogen Synthase by Pb++ results in elevated blood ALA Why

lack of heme causes de-repression of transcription of the ALA Synthase gene

ALA is toxic to the brain due to

``` • Similar ALA & neurotransmitter GABA (γ-aminobutyric acid) structures. • ALA autoxidation generates reactive oxygen species (may be) ```

is the first intermediate that includes a pyrrole ring.

Porphobilinogen

... made the condensations of the porphobilinogen 4 molecules

Porphobilinogen Deaminase

The first thing that the Porphobilinogen Deaminase do is

elimination of the amino group. In each porphobilinogen

In Porphobilinogen Deaminase has a...... prosthetic group

dipyrromethane

Porphobilinogen Deaminase (hydroxymethylbilane synthase – deficiency causes

Acute Intermittent Porphyria

converts the linear tetrapyrrole hydroxymethylbilane to the macrocyclic uroporphyrinogen III.

Uroporphyrinogen III Synthase

Uroporphyrinogen III Synthase do 2 things mention

ring closure & flipping | over of one pyrrole to yield an asymmetric tetrapyrrole

Uroporphyrinogen III is the precursor for synthesis of

vitamin B12, chlorophyll, and heme

protoporphyrin IX formation All 4 acetyl side chains are decarboxylated to methyl groups (catalyzed by

Uroporphyrinogen Decarboxylase

Uroporphyrinogen Decarboxylase – deficiency causes

Porphyria Cutanea Tarda

• Oxidative decarboxylation converts .... of 4 propionyl side chains to vinyl groups in protoporphyrin IX

``` in protoporphyrin IX Oxidative decarboxylation converts 2 of 4 propionyl side chains to vinyl groups (catalyzed by ```

Coproporphyrinogen Oxidase

Coproporphyrinogen Oxidase - deficiency | causes

Hereditary Coproporphyria

in which heme precurcer the ring regains alternating single double bonds

protoporphyrin IX

Fe++ is added to protoporphyrin IX via

Ferrocheletase

Ferrocheletase is a 1- hetrodimer contain 1 iron-sulfer cluster 2- hemodimeric contain 2 iron-sulfur clusters.

what is the reason of found a Ferrocheletase wharwese it can spontanusly chelates to many metals ?

the Ferrocheltase enzyme facilitates and accelerates the addition of Fe+2. So without this enzyme, other metals might chelate instead, and heme wont be active.

coproporphyrinonogen III | - transported back into

mitochondria

protoporphyrinogen IX converted to

protoporphyrin IX

all hereditary porphyrias are 1- autosomal dominant 2- autosomal ressesive

autosomal dominant

congenital erythropoietic porphyria is 1- autosomal dominant 2- autosomal ressesive

hepatic Porphyrias can be acute or chronic

- skin may darken, grow hair - [hypertrichosis] are a sign of

porphyrins accumelation -->photosensitivity--->Porphyrias

is | considered responsible for the neurological symptomswith some porphyrias

Elevated δ-aminolevulinic acid

Porphyria cutanea tarda manifested at later | age [ 4th or 5th decade]

``` when the ability to make new protein is decreased. but when u are young u can replace the defected proteins and have no manifestation ```

what gonna happen if one of each the following happened :: - hepatic iron overload - exposure to sunlight - hepatitis B or C - HIV

- increase in heme demand, - decrease the activity of the enzymes in pathway

symptomes of Porphyria cutanea tarda are

•cutaneous rashes, blisters •urine that is red to brown in visible light, or pink to red in UV light

•Porphyria cutanea tarda has a urine that is ..... in visible light, or ..... in UV light

red to brown | pink to red

each of the following diseases happened bcz of a mutation in specific enzyme mention

1 2 3 start

acute intermittent porphyria

hydroxymethylbilane | synthase

hereditary coproporphyria

coproporphyrinogen oxidase

variagate porphyria

protoporphyrinogen oxidase

these increase heme damands, leading to | producing precursors and their accumulation

drugs, particularly barbituates, | infection, starvation, alcohol

arsenic lead to porphyria

what is the Photodynamic Therapy

``` Destruction of unwanted cells and tissues by a combination of visible light, oxygen, light-sensitive molecules - photosensitizers ```

Heme Synthesis Flashcards

(74 cards)