Hemoglobin And Porphyrins: Biochemistry

Hemoglobin And Porphyrins: Biochemistry | Pharmacy Notes

Diksha Bhatla

Hemoglobin And Porphyrins: Biochemistry | Pharmacy Notes

16 Jul 2022

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Introduction

The structure, functions and abnormalities of haemoglobin, the synthesis and degradation of heme, the porphyrin containing compounds are discussed in this chapter.

HEMOGLOBIN

Hemoglobin (Hb) is the red blood pigment, exclusively found in erythrocytes (Greek: erythrose—red; kytos—a hollow vessel). The normal concentration of Hb in blood in males is 14–16 g/dl, and in females 13–15 g/dl. Hemoglobin performs two important biological functions concerned with respiration
1. Delivery of O₂ from the lungs to the tissues.
2. Transport of CO₂ and protons from tissues to lungs for excretion.

Structure of hemoglobin

Hemoglobin (mol. wt. 64,450) is a conjugated protein, containing globin—the apoprotein part—and the heme—the non-protein part (prosthetic group). Hemoglobin is a tetrameric allosteric protein.

Structure of globin :

Globin consists of four polypeptide chains of two different primary structures (monomeric units). The common form of adult hemoglobin (HbA1) is made up of two -chains and two -chains (22). Some authors consider hemoglobin consisting of two identical dimers—()1 and ()2. Each -chain contains 141 amino acids while -chain contains 146 amino acids. Thus HbA1 has a total of 574 amino acid residues. The four subunits of hemoglobin are held together by non-covalent interactions primarily hydrophobic, ionic and hydrogen bonds. Each subunit contains a heme group.

Structure of heme :

The characteristic red colour of hemoglobin (ultimately blood) is due to heme. Heme contains a porphyrin molecule namely protoporphyrin IX, with iron at its center. Protoporphyrin IX consists of four pyrrole rings to which four methyl, two propionyl and two vinyl groups are attached.

Heme is common prosthetic group present in cytochromes, in certain enzymes such as catalase, tryptophan pyrolase, and chlorophyll (Mg²⁺). In case of cytochromes, oxidation and reduction of iron (Fe²⁺ Fe³⁺) is essential for electron transport chain.

Other forms of hemoglobin

Besides the adult hemoglobin (HbA1) described above, other minor hemoglobins are also found in humans. In adults a small fraction (< 5%) of hemoglobin, known as HbA2 is present. HbA2 is composed of two and two (delta) chains. Fetal hemoglobin (HbF) is synthesized during the fetal development and a little of it may be present even in adults.

Hereditary persistence of fetal hemoglobin (HPFH) is a condition in which fetal hemoglobin synthesis is not terminated at birth but continues into adulthood. Glycosylated hemoglobin (HbA1c), formed by covalent binding of glucose is also found in low concentration. It is increased in diabetes mellitus which is successfully utilized for the prognosis of these patients.

Myoglobin

Myoglobin (Mb) is monomeric oxygen binding hemoprotein found in heart and skeletal muscle. It has a single polypeptide (153 amino acids) chain with heme moiety. Myoglobin (mol. wt. 17,000) structurally resembles the individual subunits of hemoglobin molecule. For this reason, the more complex properties of hemoglobin have been conveniently elucidated through the study of myoglobin.

Myoglobin functions as a reservoir for oxygen. It further serves as oxygen carrier that promotes the transport of oxygen to the rapidly respiring muscle cells.

Functions of hemoglobin

Hemoglobin is largely responsible for the transport of O₂ from lungs to tissues. It also helps to transport CO₂ from the tissues to the lungs.

Binding of O₂ to hemoglobin
One molecule of hemoglobin (with four hemes) can bind with four molecules of O₂. This is in contrast to myoglobin (with one heme) which can bind with only one molecule of oxygen. In other words, each heme moiety can bind with one O₂.

Oxygen dissociation curve :
The binding ability of hemoglobin with O₂ at different partial pressures of oxygen (pO₂) can be measured by a graphic representation known as O₂ dissociation curve.

It is evident from the graph that myoglobin has much higher affinity for O₂ than hemoglobin. Hence O₂ is bound more tightly with myoglobin than with hemoglobin. Further, pO₂ needed for half saturation (50% binding) of myoglobin is about 1 mm Hg compared to about 26 mm Hg for hemoglobin.

Cooperative binding of O₂ to hemoglobin:
The oxygen dissociation curve for hemoglobin is sigmoidal in shape. This indicates that the binding of oxygen to one heme increases the binding of oxygen to other hemes. Thus the affinity of Hb for the last O₂ is about 100 times greater than the binding of the first O₂ to Hb. This phenomenon is referred to as cooperative binding of O₂ to Hb or simply heme-heme interaction. On the other hand, release of O₂ from one heme facilitates the release of O₂ from others. In short, there is a communication among heme groups in the hemoglobin function.

Transport of O₂ to the tissues
In the lungs, where the concentration of O₂ is high (hence high pO₂), the hemoglobin gets fully saturated (loaded) with O₂. Conversely, at the tissue level, where the O₂ concentration is low (hence low pO₂), the oxyhemoglobin releases (unloads) its O₂ for cellular respiration. This is often mediated by binding O₂ to myoglobin which serves as the immediate reservoir and supplier of O₂ to the tissues

T and R forms of hemoglobin

The four subunits (22) of hemoglobin are held together by weak forces. The relative position of these subunits is different in oxyhemoglobin compared to deoxyhemoglobin.

T-form of Hb : The deoxy form of hemoglobin exists in a T or taut (tense) form. The hydrogen and ionic bonds limit the movement of monomers. Therefore, the T-form of Hb has low oxygen affinity.

R-form of Hb : The binding of O₂ destabilizes some of the hydrogen and ionic bonds particularly between dimers. This results in a relaxed form or R-form of Hb wherein the subunits move a little freely. Therefore, the R-form has high oxygen affinity.

The existence of hemoglobin in two forms (T and R) suitably explains the allosteric behaviour of hemoglobin.

PORPHYRINS

Porphyrins are cyclic compounds composed of 4 pyrrole rings held together by methenyl ( CH ) bridges Metal ions can bind with nitrogen atoms of pyrrole rings to form complexes. Heme is an iron-containing porphyrin while chlorophyll is a magnesium-containing porphyrin. Thus heme and chlorophyll are the classical examples of metalloporphyrins.

Presentation and nomenclature of porphyrins

The structure of porphyrins (C₂₀H₁₄N₄) has four pyrrole rings namely I, II, III and IV. Naturally occurring porphyrins contain substituent groups replacing the 8 hydrogen atoms of the porphyrin nucleus.

Hans Fischer, the father of porphyrin chemistry, proposed a shorthand model for presentation of porphyrin structures. Accordingly, each pyrrole ring is represented as a bracket. Thus porphyrin has 4 closed brackets with the 8 substituent positions numbered . Type I porphyrins : When the substituent groups on the 8 positions are symmetrically arranged they are known as type I porphyrins, e.g. uroporphyrin I.

Type III porphyrins : They contain asymmetric groups at the 8 positions and are more common in the biological system. Originally, Fischer placed them as IX series hence they are more popularly known as type IX porphyrins. It may be observed that the structure of uroporphyrin is asymmetric since on ring IV, the order of substituent groups is reversed (P, A instead of A, P).

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Hemoglobin And Porphyrins: Biochemistry | Pharmacy Notes

Hemoglobin And Porphyrins: Biochemistry | Pharmacy Notes

Questions

Introduction

HEMOGLOBIN

Structure of hemoglobin

Structure of globin :

Structure of heme :

Other forms of hemoglobin

Myoglobin

Functions of hemoglobin

T and R forms of hemoglobin

PORPHYRINS

Presentation and nomenclature of porphyrins

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