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Biochemistry_L2, heme synthesis part 1,2

L2, heme synthesis part 1

 Lecture video


L2 heme synthesis part 2

Lecture video



Lecture data

Heme

Is formed of ferrous protoporphyrin IX (or III).Protoporphyrin is formed of porphyrin ring in whichv arious side chains are substituted for the eighth ydrogen numbered (1 to8)

Hemoproteins

Human body contains many types of hemoproteins, which include the following:

1 Hemoglobin 2 Myoglobin

3 Cytochrome 4 Peroxidase.

5 Catalase 6 Nitric oxide synthase

7Tryptophan dioxygenase

hemoglobin


globin -In normal adult hemoglobin (Hb A)
the globin part is formed of 2alpha(α)chains and2 beta(β)chains forming tetrameric structure (α 2 β2). Each alpha chain has 141 amino acids, and beta chains have 146 aminoacid.There are 36 histidine residuesin Hb molecule

Structure


-It is composed of protein globin, to which 4 heme molecules are linked.Ferrous of heme can form5 or 6 coordination asfollow:
-Four coordination between FeII and four nitrogen of porphyrin ring.
-Fifth coordination with proximal histidine (HisF8) –sixth coordination is for oxygen.
Each heme can bind to one oxygen molecule, a hemoglobin mlecule can bind to 4 oxygen molecules 

Types of normal hemoglobin

Hemoglobin classified according to polypetide chains in globin into:

Hemoglobin A: forms (98.5%) consist of (2a &2B)

Hemoglobin A2: forms (1.5%) consist of (2a & 28).

Hemoglobin F: consist of (2a & 2y

Hemoglobin derivatives


1. Oxy hemoglobin carries oxygen present in arterial blood

2. Reduced hemoglobin present in venous blood

3. Carboxy hemoglobin carries carbon monoxide which is toxic

4. Met-hemoglobin cannot carry oxygen because the iron is present in ferric stat

N.B. NADPH + H+ resulting from HMP shunt keeps the iron of hemoglobin in the ferrous state)

Porphyria


What is the porphyria?

Congenital partial deficiency of one or more of the enzymes involved in the biosynthesis of heme (except ALA synthase) leads to:
- Decreased formation of heme.
-Releasing the enzyme ALA synthase from inhibition and causing increased production of the intermediates of heme synthesis.this usually keeps the patient compensated till the enzyme at fault is further inhibited or the requirement for heme synthesis is increased by some drugs e.g. estrogen (contraceptive pills, pregnancy), barbiturates (anticonvulsants, anesthesia), sulfonamides and griseofulvin.
These drugs require cytochrome P450 for their metabolism and hence increase the requirement for heme

Symptoms of porphyria

Two groups of manifestations can be observed in porphyri

A – Acute
porphyria

When the enzyme lesion occurs early in the pathway [PBG synthase (ALA dehydratase) or PBG deaminase (uroporphyrinogen I synthase)]
prior to formation of porphyrinogens, ALA and PBG accumulate in the body. These compounds cause toxic effects in abdominal nerves and in central nervous system, resulting in abdominal pains, peripheral neuritis and neuropsychiatric
symptoms (anxiety, depression & hallucination). This occurs in acute
intermittent porphyria due to deficiency in uroporphyrinogen I synthase

Photosensitivity

When the enzyme lesion occurs later in the pathway, this results in the accumulation of the porphyrinogens. Oxidation of porphyrinogens produces the corresponding porphyrins that cause
photosensitivity. Porphyrins when exposed to light become excited and react with oxygen to form oxygen radicals (ROS or reactive oxygen species). These radicals produce injury to lysosomes and other organelles. Damaged lysosomes release their degradative enzymes which cause variable degrees of skin damage and scarring.

As in porphyria cutanea tarda which is caused by deficiency of uroporohyrinogen decarboxylase and in hereditary coproporphyria which is caused by deficiency of coproporphyrinogen oxidaxe
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