hb synthesis and porphyrias, lecture for 1st year mbbs 3rd lec

Hemoglobin• Hemoglobin structure & synthesis

•MITOCHONDRIA & CYTOSOL MITOCHONDRIA STARTING MATERIALB6RATE LIMITING ENZYME

ALA Synthase the Key RegulatoryHepatic Biosynthesis of Heme

• It occurs – hepatic (ALAS1) – erythroid (ALAS2)

• Heme, probably acting through an aporepressor molecule, acts as a negative regulator of the synthesis of ALAS1.the rate of synthesis of ALAS1 increases greatly in the absence of heme and is diminished in its presence.

Heme also affects translation of the enzyme and its transfer

from the cytosol to the mitochondrion.• Drugs marked increase in ALAS1

erythroid form of ALAS (ALAS2)

• differs from that of ALAS1.not induced by the drugs that affect ALAS1, and it does not undergo feedback regulation by heme.

• Cytosoltwo molecules of ALA are condenses ALA dehydratase is a zinc-containing enzyme is sensitive to inhibition by lead ( lead poisoning.)

NH

pyrrole

The porphyrin ring is formed by condensation of 4 molecules of porphobilinogen. 

Porphobilinogen Deaminase catalyzes successive PBG condensations, initiated in each case by elimination of the amino group.

NH

CH2

COO

CH2

CH2

COO

H2C

NH3+

Porphobilinogen (PBG)

Porphobilinogen (PBG) is the first pathway intermediate that includes a pyrrole ring.

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PORPHYRIAS Greek “porphyros” (purple urine)

I. Enzymes Inhibitors/ deficient

II. Genetic porphyrias autosomal dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive modeMay be classified on the basis of organs or cell mostly affected either erythropoietic or hepatic On the basis of clinical features acute or cutaneous

porphyrias• abnormalities in biosynthesis of heme; • genetic or acquired. • not prevalent, but important to consider in

differential diagnosis of • abdominal pain ,• a variety of neuropsychiatric findings • photosensitivity (favoring nocturnal activities) and • severe disfigurement (congenital erythropoietic

porphyria)

• Six major types, resulting from depressions in the activities of enzymes 3 – 8

• Individuals with low activities of enzyme 1 (ALAS2) develop anemia, not porphyria.

• ALAD deficiency(lead) porphyria (excrete ALA not PBG, symptoms like (neurological).

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3) Acute intermittent porphyria ( phosphobilinogenin deaminase deficiency, the most common hepatic porphyria). 1. Symptoms - excrete PBG and ALA, high plasma PBG/AL severe abdominal pain, nausea, vomiting, hypertension(cardiovascular) then CNS - anxiety, insomnia, confusion, hallucination, then peripheral neuropathy - fatal respiratory paralysis2. a. PBG deaminase deficiency), autosomal dominant b. Genetic and precipitated by phenytoin, phenobarbital drugs, alcohol, fasting, hormones estrogen, stress, infection c. lead poisoning3. Biochemistry of neurotoxicity a. heme deficiency P450 drug metabolism

tryptophan dioxygenase brain tryptophan brain serotonin

mitochondrial cytochromes i.e. a mitochondrial disease b. ALA , mitochondrial damage, DNA damage4. Therapy - heme arginate on admission (taken up by liver not b.m.)

tryptophan

serotonin

hemedeficiency

kynuramine

Major findings in the porphyrias

Skin eruptions in a patient with porphyria cutanea tarda.