A very good morning all of you. Today we will discuss an important pathway in biochemistry that is heme synthesis. You can remember this pathway by remembering this mnemonic that is some great doctors palpate heart under cover and produces pure heme. So this is the mnemonic to remember the steps in the heme synthesis. We will discuss the steps one by one.
Before that the site for the heme synthesis it is erythroid precursor cells near about 80 percent of his heme synthesis occurs in erythroid precursor cells and remaining occur in the liver. Then it is. mitochondria and cytosol both the first enzyme that is ALA synthase it is present in the mitochondria and all oxidase that is coproporphanogen oxidase protoporphanogen oxidase and ferrochelates they are present in the mitochondria so it is partly cytosolic pathway and partly mitochondrial pathway Then we will discuss the steps in the heme synthesis. There are four important steps.
The first one is the synthesis of PAR4-B-Leno-J. Second step, the conversion of PAR4-B-Leno-J into the URO-PAR5-Leno-J. Then third, conversion of this uroporphyrinogen into protoporphyrin. And fourth one, incorporation of heme, incorporation of iron. in the protoporphyrin.
These are the four important steps in the hemoglobin synthesis. Now we will discuss one by one step in the heme synthesis. Now this is the pneumonics that is some grade. The sum it is succinyl coenzyme A and intermediate in the TCA cycle.
Condenses with the glycine. Glycine is an amino acid. In presence of enzyme, the enzyme in this state is the ALS synthase. It gives del-aminolebulinic acid. Del- aminolulonic acid.
It is written as del-aminolulonic acid. This reaction is PLP dependent. Pyridoxal phosphate is required in this reaction.
It is required to activate the glycine. Then in this reaction, there is removal of coenzyme A, there is removal of sulfhydryl group and also there is decarboxylation. There are two reactions in this, succinyl coenzyme A plus glycine gives alpha amino beta keto adipate and then this intermediate on decarboxylation is converted into delamino lipolynic acid. this tape is catalyzed by the ALA synthase so this is the some great doctors now coming to the next step in which two molecules of delaminoleonic acid condenses to form a par-4 bilinogen bilinogen purple bilinogen now this is a monopyrrole there is formation of pyrrole ring And the enzyme required in this step is ALA dehydratease. ALA dehydratease.
There is dehydration, there is removal of two water molecules. Two molecules of delamanol leulonic acid condenses with the removal of H2O. Two molecules of H2O gives PAR4 bilinol J.
Here is the formation of pyrrole ring or it is considered as monopyrrole. This one is the zinc containing enzyme and it is inhibited by the lead. This enzyme contains zinc.
This one is the zinc containing enzyme and it is inhibited by the lead. lead and Deficiency of these two enzyme ALA dehydrated and ALA synthase leads to the anemia Now coming to the parphobilinogen, which is a monopyrrole. There is formation of one pyrrole ring There is in the next step four molecules of parphobilinogen condenses with the removal of ammonia It gives a compound, the name of compound is hydroxymethyl bilane.
hydroxymethyl bilane This one is a linear tetrapyrrole, means there is formation of pyrrole ring in the first step, that is parfenogen. In the next step, there is formation of linear tetrapyrrole on deamination. This is connected by the methylene bridges. The enzyme in this tape...
conversion of parcovillinogen to hydroxymethylvillain the important enzyme is uroparcovillinogen one synthase This one is the important enzyme and deficiency of this enzyme lead to the disorder known as acute intermittent porphyria. The another name for this enzyme is HMB synthase that is hydroxymethylbenane synthase or perfobilinogen D-. There are three names of these enzymes which is important in the entrance purpose. They are deficient in the acute intermittent porphyria. The names are hydroxymethylbilin synthase or perfobilin.
immunogen D-aminase or uroparforinogen 1 synthase. Deficiency of this enzyme lead to the disorder known as acute intermittent porphyria which is characterized by the abdominal pain and neuropsychiatric manifestations. Okay, so this is some great doctors pulpit heart.
Now in the next step this hydroxymethyl bilane undergoes cyclization and there is formation of uroparphyrinogen 3. There is formation of uroparphyrinogen 3. with the help of the enzyme that is uroparphyrinogen 3 co-synthase. And deficiency of this enzyme lead to the disorder known as congenital erythropoietic porphyria. And all porphyrias are dominant except congenital erythropoietic porphyria. Okay, this is cyclization. This is linear tetrapyrrole.
This is monopyrole. Here is the formation of single pyrrole followed by the condensation. Single pyrrole which get converted into linear tetrapyrrole. with the help of four parpovirinogen molecule on deamination then on cyclization it gives uroparpovirinogen 3 okay this is the structure of uroparpovirinogen 3 these are the pyrrole rings This is the pyrrole ring and it has 8 substituent groups. That is AP, AP, AP and PA.
As it is PA here, there is change in the sequence AP, AP, AP and PA. That's why this is known as 3 in the series. That's why the name is given uroparphyrenogen 3. If it is AP, AP, AP and again AP, then it is uroparphyrenogen 1. So this is about uroparphyrenogen 3 synthesis.
After this step, this uroparthenogen 3, it gets converted into coproparthenogen. 3. Uroparfyrinogen 3 is converted into coproparfyrinogen 3 and the important enzyme in this reaction is uroparfyrinogen decarboxylase. Because decarboxylation is there, there is removal of 4 CO2, leads to the synthesis of copropylenogen 3. What happens in this step?
This is the structure we already discussed. This is the structure of uroparthalinoidin 3 that is AP, AP, AP and PA. On decarboxylation there is removal of 4 CO2 molecule. This converts this acetyl group into the methyl group. This acetyl group is converted into methyl group.
Now MPMPMPPM. So this is copropyrinogen 3 with the removal of 4 CO2 with the help of of enzyme uroparfenogen decarboxylase. This is also important enzyme.
Deficiency of this enzyme lead to the disorder known as parphyria cutanea tarda and this one is a most common parphyria, parphyria cutanea tarda with cutaneous manifestation that is photosensitivity. This photosensitivity is mainly due to the release of lysosomal enzymes hydrolysis. and that causes itching and photosensitivity on all. Now, with the help of next enzyme that is coproporphaninogen.
oxidase. As it is oxidase it is present in the mitochondria. So, unward enzyme that is coproporphanogen oxidase then next enzyme and next enzyme these three last three steps they occurs in the mitochondria.
Here also there is removal of CO2 molecule and due to the removal of CO2 molecule what happens the propionyl group which is present at the first two positions means this is a structure. there is MP MP MP PM this propionyl group it is substituted by the vinyl group and that is it is converted into MV MV MP and PM and this is known as protoporphyrinogen 9 or you can name it protoporphyrinogen 3. 3 and 9 they are same in the porphyryns. So this protoporphyrinogen 9 with the help of again under the oxidation with the help of protoporphyrinogen oxidase it get converted into protoporphyrin.
And this, after this formation of protoporphyrin, there is incorporation of iron in the ferrous form. This protoporphyrin, the iron gets center position in the pyrrole ring and it gets converted into heme. Here is the formation of heme and the important enzyme in this step is ferrochiratase.
The another name for phenotyletase is heme synthase. So this is all about heme synthesis. We will discuss one by one that is condensation of succinyl coenzyme A which is an intermediate in the TCA cycle combined with a neutral amino acid glycine with the help of pyridoxal phosphate dependent enzyme ALS.
gives del aminolavulinic acid. Two molecules of del aminolavulinic acid condenses with the help of enzyme that is zinc containing enzyme ALA dehydratease which get inhibited by the lead and gives parvovillainogen. Four molecule of parvovillainogen condenses to form hydroxymethylvillain which is a linear tetrapyrote.
After this Hydroxy-Vithylylene, it get converted into Europarfironogen 3. This Europarfironogen 3 is converted into Coproparfironogen 3, which gets converted into Protoparfironogen 9, and which is converted into Protoparfironogen 3. and iron get central position and it get converted into him. This one is the condensation reaction with the removal of CO2, coenzyme A and sulfhydryl group. This one is the removal of water molecule is here, dehydration is there. Then there is deamination with the help of Parpho-billinogen deaminase or uroparpoinogen 1 synthase or hydroxymethylbillinase synthase.
So three names of the same enzyme. Here this linear tetrapyrrole undergoes cyclization with the help of co-synthase enzyme and use uroparpoinogen 3, which on decarboxylation means acetyl group is converted into methyl group use coproparpoinogen 1, Then Propionyl groups which are present on the first and second position they get converted into Vinyl group and we get Protoporphyrin 9 and this Protoporphyrin 9 is converted into Protoporphyrin which is converted into Heme. The iron gets central position and it is converted into Heme. So remember the mnemonic. Some great doctors.
doctors, pulpit heart under cover produces pure hip. We will discuss or we will summarize the entire pathway in one diagram. We will discuss the porphyria in next lecture in detail.
Okay. This is succinyl coenzyme A plus glycine. It gives delaminolivulanic acid. Condensation of delaminolivulanic acid gives paracobilinogen.
4 molecules of perfluorinogen combine to give hydroxy methylpylene then it get converted into uroparfluorinogen 3 it gets converted into coproporphyrinogen 3 then it gets converted into protoporphyrinogen 9 it is converted into protoporphyrin and it gets converted into heme ok now the important enzyme in this is the ALA synthase There are two types of ALA synthase. One is present in the erythroid cell, erythroid precursor cell. The synthesis of him occurs in all cell except matured RBC. ALA synthase 1 and ALA synthase 2 is there.
ALA Synthase 1 is present in the erythrit precursor cell. It is an inducible enzyme. Various drugs induces the concentration of ALA Synthase and Heme Synthesis. Also it is sub- It is a rate limiting and regulatory step in this pathway and it is regulated by the feedback inhibition and also by the repression and control of transport across the mitochondria. ALA transport across the mitochondria is also regulated.
So this one is the important enzyme ALA synthet. Then second one is the ALA dehydratease. These are the two important enzymes.
Then U1, U3, UD. These are the enzymes. That is uroparphylenogen 1 synthase, uroparphylenogen 3 cosynthase, uroparphylenogen decarboxylase, then coproparphylenogen oxidase, then protoparphylenogen oxidase and ferrogylet. These are the important enzymes that is uroporphyrinogen synthase.
The another name is parphoginogen DMINase or hydroxymethylbirane synthase. This is uroporphyrinogen 3 co-synthase. then uroporphanogen dicarboxylase then coproporphanogen oxidase protoporphanogen oxidase and the last one is the ferrochilates or heme synthase so these are the important enzymes in the heme synthesis one two three four five six seven eight now coming to the important porphyria there are two types of porphyria hepatic and erythroid porphyria so this one is the this enzyme is inhibited by the lead Deficiency of uroparfarinogen synthase lead to the disorder known as acute intermittent porphyria.
This one is the most common acute disorder characterized by abdominal pain and neuropsychiatric manifestations. then uroparthinogen 3 co-synthase leads to the disorder known as congenital erythropoietic parphyria this is the only parphyria which one is autosomal recessive all are autosomal dominant then urocarb Porphyrinogen decarboxylates lead to the porphyria cutanea tarda. This one is the most common porphyria and it having cutaneous manifestation that is photosensitivity. Then coproporphyrinogen oxidase mitochondrial enzyme.
It lead to the disorder known as hereditary coproporphyrinogen. Then next one is the protoporphyrinogen oxidase deficiency of this enzyme lead to the disorder known as. Irithru poetic Irithru poetic porphyria Deficiency of this protoporphyrinogen oxidase leads to the disorder known as virigate porphyria.
Virigate porphyria and ferrochelitis enzyme deficiency lead to the disorder known as protoporphyria. So these are the various porphyrias in which porphyria and various intermediates are excreted in the urine. Acute intermittent porphyria, congenital erythropoietic porphyria, porphyria cutanea dada, hereditary coproporphyria, variegate porphyria and protoporphyria. This is all about the heme synthesis.
We will discuss the porphyria in our next video lecture. Keep watching. If you like the video, please hit the like button and subscribe to the channel. Thank you all of you.
Thank you very much.