Haem, biosynthesis

During the second part of the experiment the examined compounds were applied repeatedly both to mice and rats. The same parameters, as after single administration were estimated in the serum and liver. Additionally, ALA-D and ALA-S, the two enzymes from haeme biosynthesis pathway were evaluated in the liver. 

Figure 7.1 The overall pathway of haem biosynthesis. 5-AminolaevuIinate (ALA) is synthesized in the mitochondrion, and is transferred to the cytosol where it is converted to porphobilinogen, four molecules of which condense to form a porphyrin ring. The next three steps involve oxidation of the pyrrole ring substituents to give protoporphyrinogen fX, whose formation is accompanied by its transport back into the mitochondrion. After oxidation to protoporphyrin IX, ferrochelatase inserts Fe2+ to yield haem. A, P, M and V represent, respectively acetyl, propionyl, methyl and vinyl (—CH2=CH2) groups. From Voet and Voet, 1995. Reproduced by permission of John Wiley Sons, Inc.

IX is accompanied by its transport back into the mitochondria whence it came, to undergo oxidation of its methylene groups to protoporphyrin IX and insertion of iron to yield the end product, haem. The two major sites of haem biosynthesis are erythroid cells, which synthesize around 85 % of the body s haem groups, and the liver, which synthesizes most of the remainder. A major function of haem in liver is as the prosthetic group of cytochrome P450, the importance of which in detoxification has been discussed in Chapter 2. The liver cell must synthesize cytochrome P450 throughout its lifetime in quantities that vary with conditions. In contrast, the... 

Zinc protoporphyrin IX is a normal metabolite that is formed in trace amounts during haem biosynthesis. However, in iron deficiency or in impaired iron utilization, zinc becomes an alternative substrate for ferrochelatase and elevated levels of zinc protoporphyrin IX, which has a known low affinity for oxygen, are formed. This zinc-for-iron substitution is one of the first biochemical responses to iron depletion, and erythrocyte zinc protoporphyrin is therefore a very sensitive index of bone-marrow iron status (Labbe et ah, 1999). In addition, zinc protoporphyrin may regulate haem catabolism by acting as a competitive inhibitor of haem oxygenase, the key enzyme of the haem degradation pathway. However, it has been reported... 

Finally, in this last group, we include lead that causes saturnism7, particularly among young children in socially deprived inner cities. The toxicity of environmental Pb finds its molecular explanation in the extraordinary high affinity of Pb (binding constant of 1015 M) for the key Zn-dependent enzyme of haem biosynthesis, porphobilinogen synthase. 

The porphyrias are a heterogeneous group of inherited disorders of haem biosynthesis. Figure A9.1 shows the pathway of haem synthesis. A deficiency in one of the enzymes results in a specific porphyria. 

Fig. 41. Proposed mechanism for the retentive decarboxylation of acetic acid side chain during haem biosynthesis.

The first sub-cellular organelle to be isolated (other than the nucleus), mitochondria are the powerhouse of the cell, generating ATP through aerobic oxidative phosphorylation the TCA (Krebs) cycle (the hub of metabolism ) and fatty acid oxidation take place entirely within mitochondria. Other pathways and cycles (urea cycle, haem biosynthesis, cardiohpin synthesis, quinone and steroid biosynthesis) include steps both outside and inside the mitochondria. 

Panek H, O Brian MR. A whole genome view of prokaryotic haem biosynthesis. Microbiology 2002 148(Pt 8) 2273-2282. 

Rimington, C. (1989) Haem biosynthesis and porphyrias 50 years in retrospect, J. Clin. Chem. Clin. Biochem., 27 473 -86. 

Acute intermittent porphyria The porphyrias are disorders of haem biosynthesis. The acute porphyrias which present with abdominal pain and neurological features all have increased urinary porphobilinogen during an attack, and this is diagnostic... 

Smith et al. (1995) reported synergy of iron in the toxicity and carcinogenicity of PCBs. An iron overload induced liver tumors and other lesions in mice. A single dose of iron potentiated PCB mixture Aroclor 1254 to induce porphyria by inhibition at the uroporphyrinogen decarboxylase stage of hepatic haem biosynthesis. The authors proposed an iron-catalyzed oxidative stress mechanism suggesting a link between porphyria and cancer. 

Alterations in the activity of the enzymes of haem biosynthesis in lead poisoning and acute hepatic pwrphyria. Clin. Sci. Mol. Med. 1977 53 335-340. 

Goldberg, A. Lead poisoning and haem biosynthesis. Br.. Haematol, 1972,23 521-524. Goldberg, A., Meredith, PA., Miller, S., Moore, MR. Thomson, GG. Hepatic drug metabolism and haem biosynthesis in lead poisoned rats. Br. f. Pharmacol. 1978, 62 ... 

Meredith, PA. Moore, MR. Goldberg, A. Erythrocyte 8-aminolevulinic acid dehydratase activity and blood Protoporphyrin concentrations as indices of lead exposme and altered haem biosynthesis. Clin. Sci 1979 56 61-69. 

Lead inhibits PBG synthase and ferrochelatase, restricting haem biosynthesis and resulting in microcytic hypochromic anaemia and porphyria. Urinary excretion of 5-ALA is increased. 

Haematology - Sideroblastic anaemia is a known side effect of both INH and PZA as they inhibit the enzyme 5-aminolevulinic acid synthase-2, catalysing the first step of haeme biosynthesis [63, 64 ]. 

---