Module 6.2: Hemoglobin Synthesis and Function

PART 2

Main Function of the Hemoglobin

• O2 delivery to tissues

• Transport waste products like CO2

Hemoglobin

• Synthesized within maturing erythrocytes

• Metalloprotein

• Composed of four polypeptide chain with its own heme

• Maintaining blood pH

Globin

4 polypeptide chains which comes in dimers, a total of 2 dimers

• Protoporphyrin IX

• Iron atoms (Fe2+)

Heme-Component

One (1) 2-3 diphosphoglycerate (2-3DPG)

Has a role in the oxygen binding capacity of the Hemoglobin.

5-aminolevulinic acid

succinyl-CoA and glycine forms?

pyrrole molecule

uccinyl-COA binds with glycine to form?

protoporphyrin IX

four pyrroles combine to form?

heme molecule

protoporphyrin IX, which then combines with iron to form?

16,000 Daltons

Each chain has a molecular weight of about?

Globin Chains

• Varied sequence of amino acids polypeptide chains

• Changes during fetal life and early infant life

• Changes also after birth

• Gower 1 (ζ2ε2)

• Gower 2 (α2ε2)

• Hemoglobin Portland (ζ2γ2)

Non-Pathological Variants of Hemoglobin In the Embryo

Hemoglobin F (α2γ2)

Non-Pathological Variants of Hemoglobin In the Fetus

• Hemoglobin A (α2β2)

• Hemoglobin A2 (α2δ2)

• Hemoglobin F F (α2γ2)

Non-Pathological Variants of Hemoglobin In the Adults

Hemoglobin A (α2β2)

The most common with a normal about 97% in adult (newborn 20%).

Hemoglobin A2 (α2δ2)

chain synthesis begins late in the third trimester and in adults, it has a normal range up to 2.5% (<0.5%NB)

Hemoglobin F F (α2γ2)

In adults Hemoglobin F is restricted to a limited population |F-cells

<1%

Hemoglobin F Proportion in Normal Adult (%)

97 – 98%

Hemoglobin A (α2β2) Proportion in Normal Adult (%)

2-3%

Hemoglobin A2 (α2δ2) Proportion in Normal Adult (%)

Primary Globin Structure

• globin structure specific sequence of Aa residues

• Alpha chain is numbered 1-141

• 1 (N-terminal) to; 141 (C-terminal) chain

Secondary Globin Structure

globin structure is divided into 8 separate helical segments designated as A-H which gives the rigidity to structures

α

Stronger Bonders

β

Lesser Strength / Weaker

T form

• Beta chains are farther apart

• Decrease affinity to O₂

R form

• B chains move closer together

• Increase affinity to O2

5-aminolevulinic acid (ALA)

What makes up of these pyrrole molecules?

Heme

• imparts the red color

• comprised of protoporphyrin IX and iron (reduced form – ferrous)

Tetramethenetetrapyrrole

cyclic compound consists of 4 pyrrole rings (A, B, C & D)

Protoporphyrin IX

What is the last compound leading to production of heme?

• Iron (Reduced Form – Ferrous)

• Ferrochelatase Enzyme

What do you need in order for Protoporphyrin IX to convert to Heme?

Free Erythrocyte Protoporphyrin (FEP)

protoporphyrin that was not converted is called

Liver

Where is iron usually stored?

Ferritin

Storage form of Iron

Prussian Blue Reaction

What is process of estimating the stored forms of iron?

Hemosiderin

If apoferritin is unavailable iron is stored as?

duodenum and jejunum

Where is iron mostly absored?

Hydrochloric acid in the stomach

reduction of Ferric to Ferrous is accomplished by the?

10%

How much of dietary iron is absorbed by mucosal cells oxidized to Fe+3 then stored temporarily to cells as ferritin?

Ferritin Transferrin

When iron is needed Fe+3 is released by intestinal mucosal cells then attaches to transferrin as?

Protoporphyrin lX

Synthesized in mitochondria and partly cytoplasm of nucleated red cells.

Porphyrias

Any deficiency or defects in these enzymes in the production of Heme, would result to a certain group of condition we call as?

ALA Hydratase deficiency porphyria

Disease in Aminolevulinic acid synthetase deficiency

Acute intermittent porphyria

Disease in Uroporphyrinogen synthase deficiency

Congenital erythropoietic porphyria

Disease in Uroporphyrinogen cosynthase deficiency

Porphyria cutanea tarda

Disease in Uroporphyrinogen decarboxylase deficiency

Hereditary coproporphyria

Disease in Coproporphyrinogen oxidase deficiency

Variate porphyria

Disease in Protoporphyrinogen oxidase deficiency

Erythropoietic protoporphyria

Disease in Ferrochelatase deficiency

2

Lead Exposure Stage of ALA Hydratase deficiency porphyria?

8

Lead Exposure Stage of Erythropoietic protoporphyria?

Elevated Compound: ALA Porphobilinogen

Clinical Symptoms: Neurologic / Psychiatric

Laboratory Testing: Urine / Ehrlich Reaction

Acute intermittent porphyria

Elevated Compounds?

Clinical Symptoms?

Laboratory Testing?

Elevated Compounds: Uroporphyrin

Clinical Symptoms: Photosensitivity

Laboratory Testing: Urine Fluorescence

Porphyria cutanea tarda

Elevated Compounds?

Clinical Symptoms?

Laboratory Testing?

Elevated Compounds: Uroporphyrin, Coproporphyrin

Clinical Symptoms: Photosensitivity

Laboratory Testing: Urine or Feces Fluorescence

Congenital erythropoietic porphyria

Elevated Compounds?

Clinical Symptoms?

Laboratory Testing?

Elevated Compounds: Coproporphyrin

Clinical Symptoms: Photosensitivity / Neurologic

Laboratory Testing: Bile or Feces Fluorescence

Variegate porphyria

Elevated Compounds?

Clinical Symptoms?

Laboratory Testing?

Elevated Compounds: Protoporphyrin

Clinical Symptoms: Photosensitivity

Laboratory Testing: Blood FEP Bile or Feces Fluorescence

Erythropoietic protoporphyria

Elevated Compounds?

Clinical Symptoms?

Laboratory Testing?

Elevated Compounds: a. ALA b. Proporphyrin

Clinical Symptoms: Neurologic

Laboratory Testing:

ALA: Acetoacetic acid + Urine / Ehrlich Reaction

Protoporphyrin: Blood FEP

Lead Poisoning

Elevated Compounds?

Clinical Symptoms?

Laboratory Testing?