Heme Synthesis

Question 1

What are porphyrins?

Answer 1

They are cyclic compounds that bind metal ions. Such as heme.

Question 2

What are the components of heme

Answer 2

A ferrous ion in the center, a protophyrin IX ring.

Question 3

Heme acts as a prosthetic group to ?

Answer 3

Hemoglobin (heme + globus proteins) , myoglobin, cytochrome, tryptophan pyrrolase

Question 4

What are cytochromes? What are the 3 kinds and how can we distinguish them?

Answer 4

They are electron transporting heme proteins. They have 3 different forms : Heme A(has an isoprenoid moiety, for the noncovalent interactions with cytochrome a) , Heme B (is the iron-protoporphyrin IX found in Hb), Heme C (the pyrrol ring has covalent interactions with proteins thanks to Cys residues).
We can distinguish them by differing absorption spectrum.

Question 5

What are porphyrins?

Answer 5

They are cyclic molecules, made of 4 pyrrol rings which are linked by methenyl bridges

Question 6

What are the side chains present in protoporphyrin IX . What type of side chain organisation does it have?

Answer 6

Vinyl, methyl, propripnate. It has a type III organisation

Question 7

What are porphyrinogens

Answer 7

They are a porphyrin precursor.

Porphobilinogen–porphyrinogens–protoporphyrins

Question 8

What determines the type of porphyrin

Answer 8

The position of the side chains. In type III the acetate and proprionate are exchanged in position on a single moiety

Question 9

What does iron protoporphyrin IX derive from? What does it bind to?

Answer 9

Its a derivative of protoporphyrin IX, it binds metals like Fe2+ (heme-ferrous), Fe3+ (hemin-ferric), Zinc protoporphyrin Zn2+

Question 10

Where does heme synthesis occur?

Answer 10

Occurs in the mitochondrial matrix and cytoplasm of all cells.

Question 11

list the overall pathway of heme synthesis

Answer 11

succinyl-coA and glycine. ALA SYNTHASE. aminolevulinic acid. porphobilinogen.
uroporphyrinogen III.
coproporphyrinogen III
protoporphyrinogen IX.
protoporphyrin IX.
Heme

Question 12

what is the rate limiting step of heme synthesis.

Answer 12

first step. Glycine and Succinyl coA. condense together. Enzyme aminolevulinate synthase.
it is inhibited by heme and hemin.
there is the release of coA and co2

Question 13

What is inhibited by heme and hemin in the liver?

Answer 13

they inhibit ALA synthase synthesis, rate of translocation from cytosol to mitochondria, and the activity of ALA synthase

Question 14

the activity of ALA synthase depends on?

Answer 14

it responds to the detoxification needs,

Question 15

what kind of amino acid aminolevulinic ? Where is it formed?

Answer 15

its a non essential amino acids. In the mitochondria

Question 16

what does heme do in reticulocytes?

Answer 16

it stimulates the synthesis of globins and the enzymes of its own biosynthetic pathway

Question 17

what kind of amino acid is glycine?

Answer 17

non essential amino acid

Question 18

what is the coenzyme needed for the rate limiting step?

Answer 18

pyridoxal phosphate, is needed for the decarboxylation of glycine

Question 19

what regulates the level of ALA synthase?

Answer 19

iron and protohemin

Question 20

what is hemin?

Answer 20

when there is excess heme, it is converted to hemin. This decreases the action of ALA synthase. It is an example of end product inhibition

Question 21

what is the function of grisofulvin, antifungal or anticonvulsant drugs?

Answer 21

they increase ALA synthase activity. This is because they are metabolized in the liver by cytochrome p450 and consume heme.

Question 22

what is the second step of heme synthesis.

What enzyme catalyses it?

Answer 22

the formation of porphobilinogen from the condensation of 2 molecules of ALA. It is catalyzed by porphobilinogen synthase/ ALA dehydratase. It is dependent on Zn.

Question 23

ALA dehydratase is inhibited by?

Answer 23

Pb, resulting in anemia or lead poisoning. When this occurs ALA in blood is elevated

Question 24

how is protoporphyrin IX formed?

Answer 24

porphobilinogen is changed to hydroxymethylbilane, which forms uroporphyrinogen III, whose side chains are modified to form protoporphyrin IX

Question 25

what are steps 3,4,5 of heme synthesis?

Answer 25

tetrapyrrole formation. conversion to protoporphyrin III. protoheme synthesis

Question 26

how is protoporphyrin IX turned into heme?

Answer 26

``` ferrous ions (Fe2+) are introduced into protoporphyrin IX by ferrochelatase ```

Question 27

how is hemoglobin formed?

Answer 27

protoheme + globin

Question 28

what is the consequence of protohemin formation?

Answer 28

formation of super oxides

Question 29

when is protohemin formed from protoheme?

Answer 29

when the O2 added is negatively charged. SO its Fe3+

Question 30

refer to slide 25 for regulation of porphyrin synthesis?

Answer 30

do itttt

Question 31

what is porphyria?

Answer 31

they are rare inherited defects in heme synthesis. An inherited defect in an enzyme of heme synthesis results in accumulation of one or more of the porphyrin precursors depending on where the blocking is in the heme synthesis pathway. These precursors increase in blood and appear in urine of affected individuals. Porphyria means purple colour caused by the pigment-like porphyrins in the urine. (Diagnosed by lab investigation) Most porphyrias show a prevalent autosomal dominant pattern, except congenital eythropoietic porphyria, which is recessive

Question 32

what are the 2 kinds of porphyria?

Answer 32

erythropoietic and hepatic (hepatic can be acute or chronic)

Question 33

know that

Answer 33

Generally, individuals with an enzyme defect prior to the synthesis of the tetrapyrroles manifest abdominal and neuropsychiatric signs Those with defects after the synthesis of tetrapyrrole intermediates show photosensitivity with formation of reactive oxygen species (ROS) that damage membranes by oxidation resulting in the following effects: - Skin blisters, itches (pruritis) - Skin may darken, hair growth (hypertrichosis)

Question 34

go to slide 28

Answer 34

pls

Question 35

what is the most common type of porphyria and what is it caused by?

Answer 35

Chronic hepatic porphyria (porphyria cutanea tarda) • The most common type of porphyria • a deficiency in uroporphyrinogen decarboxylase • Clinical expression of the enzyme deficiency is influenced by various factors, such as exposure to sunlight, the presence of hepatitis B or C • Clinical onset is during the fourth or fifth decade of life. • Porphyrin accumulation leads to cutaneous symptoms and urine that is red to brown in natural light and pink to red in fluorescent light

Question 36

discuss acute hepatic porphyrias?

Answer 36

Porphyrias leading to accumulation of ALA and porphobilinogen cause abdominal pain and neuropsychiatric disturbances, ranging from anxiety to delirium. • Symptoms of the acute hepatic porphyrias are often precipitated by administration of drugs such as barbiturates and ethanol.

Question 37

what is the treatment of porphyrias?

Answer 37

hematin (hemin hydroxide)