Harpers

Porphyrins & Bile Pigments 32Robert K. Murray, MD, PhDBIOMEDICAL IMPORTANCEThe biochemistry of the porphyrins and of the bile pigmentsis presented in this chapter. These topics areclosely related, because heme is synthesized from porphyrinsand iron, and the products of degradation ofheme are the bile pigments and iron.Knowledge of the biochemistry of the porphyrinsand of heme is basic to understanding the varied functionsof hemoproteins (see below) in the body. Theporphyrias are a group of diseases caused by abnormalitiesin the pathway of biosynthesis of the various porphyrins.Although porphyrias are not very prevalent,physicians must be aware of them. A much more prevalentclinical condition is jaundice, due to elevation ofbilirubin in the plasma. This elevation is due to overproductionof bilirubin or to failure of its excretion andis seen in numerous diseases ranging from hemolyticanemias to viral hepatitis and to cancer of the pancreas.METALLOPORPHYRINS& HEMOPROTEINS AREIMPORTANT IN NATUREPorphyrins are cyclic compounds formed by the linkageof four pyrrole rings through ⎯HC ⎯ methenylbridges (Figure 32–1). A characteristic property of theporphyrins is the formation of complexes with metalions bound to the nitrogen atom of the pyrrole rings.Examples are the iron porphyrins such as heme of hemoglobinand the magnesium-containing porphyrinchlorophyll, the photosynthetic pigment of plants.Proteins that contain heme (hemoproteins) arewidely distributed in nature. Examples of their importancein humans and animals are listed in Table 32–1.Natural Porphyrins Have Substituent SideChains on the Porphin NucleusThe porphyrins found in nature are compounds inwhich various side chains are substituted for the eighthydrogen atoms numbered in the porphin nucleusshown in Figure 32–1. As a simple means of showingthese substitutions, Fischer proposed a shorthand formulain which the methenyl bridges are omitted andeach pyrrole ring is shown as indicated with the eight270substituent positions numbered as shown in Figure32–2. Various porphyrins are represented in Figures32–2, 32–3, and 32–4.The arrangement of the acetate (A) and propionate(P) substituents in the uroporphyrin shown in Figure32–2 is asymmetric (in ring IV, the expected order ofthe A and P substituents is reversed). A porphyrin withthis type of asymmetric substitution is classified as atype III porphyrin. A porphyrin with a completely symmetricarrangement of the substituents is classified as atype I porphyrin. Only types I and III are found in nature,and the type III series is far more abundant (Figure32–3)—and more important because it includes heme.Heme and its immediate precursor, protoporphyrinIX (Figure 32–4), are both type III porphyrins (ie, themethyl groups are asymmetrically distributed, as in typeIII coproporphyrin). However, they are sometimesidentified as belonging to series IX, because they weredesignated ninth in a series of isomers postulated byHans Fischer, the pioneer worker in the field of porphyrinchemistry.HEME IS SYNTHESIZED FROMSUCCINYL-COA & GLYCINEHeme is synthesized in living cells by a pathway that hasbeen much studied. The two starting materials are succinyl-CoA,derived from the citric acid cycle in mitochondria,and the amino acid glycine. Pyridoxal phosphateis also necessary in this reaction to “activate”glycine. The product of the condensation reaction betweensuccinyl-CoA and glycine is α-amino-β-ketoadipicacid, which is rapidly decarboxylated to form α-aminolevulinate(ALA) (Figure 32–5). This reaction sequenceis catalyzed by ALA synthase, the rate-controlling enzymein porphyrin biosynthesis in mammalian liver.Synthesis of ALA occurs in mitochondria. In the cytosol,two molecules of ALA are condensed by the enzymeALA dehydratase to form two molecules of waterand one of porphobilinogen (PBG) (Figure 32–5). ALAdehydratase is a zinc-containing enzyme and is sensitiveto inhibition by lead, as can occur in lead poisoning.The formation of a cyclic tetrapyrrole—ie, a porphyrin—occursby condensation of four molecules ofPBG (Figure 32–6). These four molecules condense in ahead-to-tail manner to form a linear tetrapyrrole, hy-