Disorders of haemoproteins, porphyrins and iron

Chapter 17 Disorders of haemoproteins, porphyrins and iron


Haemoglobin and haemoglobinopathies

Haemoglobin is a very accessible protein and has been studied extensively. The haemoglobinopathies (genetically determined abnormalities of haemoglobin synthesis) fall into two groups: qualitative, most frequently involving amino acid substitutions, and quantitative disorders, known as ‘thalassaemias’.

Abnormal derivatives of haemoglobin


Protoporphyrin IXα, which combines with iron to form haem, is the end product of a series of complex reactions. The first step that is unique to this pathway is the combination of glycine and succinyl CoA to form δ-aminolaevulinic acid (ALA), a reaction catalysed by the enzyme ALA synthase (Fig. 17.2). Two molecules of ALA then condense to form porphobilinogen (PBG), in a reaction catalysed by PBG synthase (also known as ALA dehydratase).

The first porphyrins (strictly, porphyrinogens, see below) are formed when four molecules of PBG condense together. The initial product of this reaction, catalysed by hydroxymethylbilane synthase (PBG deaminase) is hydroxymethylbilane. In the presence of uroporphyrinogen III cosynthase (also known as ‘uroporphyrinogen III synthase’), this is converted to uroporphyrinogen III. In the absence of this enzyme, hydroxymethylbilane is converted non-enzymatically to uroporphyrinogen I. A series of enzyme-catalysed reactions through isomers of the III series leads to the formation of protoporphyrin IXα. Haem is formed when iron is incorporated into this molecule in a reaction catalysed by ferrochelatase.

The porphyrinogens are themselves unstable and become oxidized to their corresponding porphyrins when they are excreted in faeces or urine. Porphyrinogens and porphyrin precursors are colourless. Porphyrins are dark red in colour and intensely fluorescent. The major sites of porphyrin synthesis are the liver and the erythroid bone marrow.

The rate-limiting step in this sequence of reactions is the first, catalysed by ALA synthase, which is susceptible to inhibition by the end product, haem.

The porphyrias

These are a group of inherited diseases in which a partial deficiency of one of the enzymes of porphyrin synthesis leads to decreased formation of haem and thus, by releasing ALA synthase from inhibition, results in the formation of excessive quantities of porphyrin precursors (ALA and PBG) or porphyrins. When precursors are produced in excess, the clinical manifestations are primarily neurological (the precursors are neurotoxins). When porphyrins themselves are the major product, the predominant feature is photosensitivity: the porphyrins absorb light and become excited, inducing the formation of toxic free radicals. The porphyrias are diagnosed on the basis of their clinical features and the pattern of porphyrins and precursors present in blood and excreted in faeces and urine.

The porphyrias are classified as acute or non-acute, according to their clinical presentation, and hepatic or erythropoietic, depending on the major site of abnormal metabolism (Fig. 17.3). All the porphyrias are rare. Cutaneous hepatic porphyria (also known as porphyria cutanea tarda) is the most common but many cases are not inherited. Of the purely genetic types, acute intermittent porphyria is the most common, with a prevalence in the UK, where it occurs more frequently than in many countries, of 1–2 cases per 100 000 of the population. Unusually for inherited metabolic diseases, the mode of inheritance of most porphyrias is autosomal dominant, the exceptions being congenital erythropoietic porphyria, ALA dehydratase deficiency porphyria and hepatoerythropoietic porphyria (autosomal recessive). The features of the porphyrias are summarized in Figure 17.4. The genes for the enzymes involved in porphyrin synthesis have been identified and cloned, but the porphyrias are genetically heterogeneous; this hinders the application of molecular biological techniques to the identification of carriers and to screening for porphyrias.

Acute porphyrias

Acute intermittent porphyria (AIP) is the commonest of these. Photosensitivity is never a feature of AIP, although it may occur in patients with hereditary coproporphyria and variegate porphyria.

Clinical features

These conditions are characterized by a tendency to acute attacks, separated by long periods of complete remission. The clinical features of acute attacks are summarized in Figure 17.5. Abdominal pain and psychiatric disturbances are nearly always present; peripheral neuropathy occurs in some 60% of patients. Attacks can be precipitated by various factors, including many drugs (see Fig. 17.5); most frequently implicated are barbiturates, oral contraceptives and alcohol. These probably act by increasing the activity of ALA synthase, in many cases by increasing the synthesis of hepatic cytochrome P450 and hence the demand for haem, thereby decreasing intrahepatic haem concentration and releasing the enzyme from inhibition. Some drugs, notably the sulphonamides, inhibit PBG deaminase directly. Whatever the cause, the resulting increased activity of the metabolic pathway increases the formation of metabolites before the enzyme block.

Hormonal factors are also extremely important; symptoms rarely occur before puberty and may fluctuate in relation to menstruation or pregnancy. Women are affected more commonly than men. In some 90% of individuals who inherit the defective gene for AIP, the disease remains clinically latent throughout adult life.

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Apr 3, 2019 | Posted by in BIOCHEMISTRY | Comments Off on Disorders of haemoproteins, porphyrins and iron

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