Haem synthesis

Elder GH Haem synthesis and the porphyrias. In Scientific Foundations of Biochemistry in Clinical Practice, 2nd ed. Williams DL, Marks V (editors). Butterworth-Heinemann, 1994. 

Tenhunen R, Savolainen H, Jappinen P. 1983. Changes in haem synthesis associated with occupational exposure to organic and inorganic sulphides. Clin Sci 64 187-191. 

Nitric oxide and eicosanoid synthesis haem synthesis. The importance of the pentose phosphate pathway reduced glutathione in maintaining red cell integrity. The respiratory burst in phagocytes. Clotting and complement enzyme cascades. Metabolism of lipoproteins. 

Red blood cells are amongst the most numerous of the human cell lines an average healthy 70 kg male having a total of approximately 25 x cells in his 51 of blood. A typical red cell contains in excess of 600 million haemoglobin molecules which equates to a total of about 300 g of haemoglobin, an amount that is far greater than for any other protein in the body. The lack of a nucleus clearly indicates that red cells cannot divide and at the end of their life, worn out RBCs are removed by the cells of the reticuloendothelial system. Approximately 2% (5 x 1011) of the red cell number are removed and replaced by new ones each day. Haem synthesis is outlined later in this chapter and its catabolism is discussed in Chapter 6. 

Circulating RBCs lack the enzymes to produce either haem groups or globin chains so the synthesis of haemoglobin is a defining feature of early RBC maturation. Globin chain production is like the formation of any other protein, but a and 3 chain synthesis is closely linked with haem synthesis. 

Haem synthesis is a good example of a pathway that is partly compartmentalized. The pathway (Figure 5.16) occurs in all cell types for the production of respiratory cytochromes and begins within mitochondria but the majority of the reactions occur in the cytosol cell. Because mature red cells have no subcellular organelles, haem synthesis occurs only in early RBC progenitor cells. Although this is a relatively simple pathway, there are a number of well-known enzyme defects that cause a group of diseases called the porphyrias. 

Figure 5.16 Haem synthesis. NB PBG is converted into two forms of uroporhyrinogen, the series I and III isomers but only the series III compounds are physiologically important...

In addition to the common pathways, glycolysis and the TCA cycle, the liver is involved with the pentose phosphate pathway regulation of blood glucose concentration via glycogen turnover and gluconeogenesis interconversion of monosaccharides lipid syntheses lipoprotein formation ketogenesis bile acid and bile salt formation phase I and phase II reactions for detoxification of waste compounds haem synthesis and degradation synthesis of non-essential amino acids and urea synthesis. 

All tissues except mature red blood cells are able to manufacture haem for use in the respiratory cytochrome proteins of the electron transport chain. However, the liver is an especially important site of haem synthesis because it (a) is a major organ of erythropoiesis in utero and (b) haem-containing cytochrome-P450 (CYP-450) enzymes play significant roles in hepatic detoxification of drugs, toxins and endogenous waste products (Section 6.4). 

Haem synthesis All cells, liver and red blood cell precursors especially Partly in cytosol and partly within mitochondria 5.3.1.3, 6.3.3... 

Figure 15.20 Control of the rate of haem synthesis. The concentration of the enzyme aminolevulinic acid synthase, the first enzyme in the synthesis of haem, and the flux-generab ng enzyme, is increased by IRP. This ensures an adequate rate of synthesis of haem, even though the iron level in the cell may be low. This is achieved by stimulation of translation. Full details of the pathway are presented in Appendix 15.3.

Section M Smil, V. (1997) Global population and the nitrogen cycle. Sci. Amer. 277(7), 58-63. Warren, M.J., Cooper, J.B., Wood, S.P. and Shoolingan-Jordan, P.M. (1998) Lead poisoning, haem synthesis and 5-aminolaevulinic acid dehydratase. Trends Biochem. Sci. 23, 217-221. Warren, M.J. and Scott, A.I. (1990) Tetrapyrrole assembly and modification into the ligands of biologically functional cofactors. Trends Biochem. Sci. 15, 486-491. 

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. 

Figure A9.1 Pathway of haem synthesis. Blocks at various parts of the pathway result in different porphyrias (numbers in parentheses show inheritance). AR, autosomal recessive AD, autosomal dominant. (From Thadani et al., 2000, reproduced with permission.)...

Q2 Amino acids are needed to produce the plasma membrane Bi2 (cyanocobal-amine), which is stored in the liver, is required for synthesis of DNA. Folic acid is also needed for synthesis of DNA (it is a component of thymine, adenine and guanine) and for RNA synthesis. Other B vitamins are required for haem synthesis and oxidative metabolism. Iron is required in ferrous form for haemoglobin synthesis vitamin C helps maintain iron in its ferrous form. 

Haem synthesis defect, for example iron-deficiency anaemia and anaemia of chronic disease (more commonly presenting as normocytic anaemia). 

In healthy people, forming haemoglobin for their erythrocytes and haem-dependent enzymes, the rate of haem synthesis is controlled by negative feedback according to the amount of haem present. When more haem is needed there is increased production of the rate-controlling enzyme delta-aminolaevulinic acid (ALA) synthase which provides the basis of the formation of porphyrin precursors of haem. But in people with porphyria one or other of the enzymes that convert the various porphyrins to haem is deficient and so porphyrins accumulate. A vicious cycle occurs less haem —> more ALA synthase —> more porphyrin precursors, the metabolism of which is blocked, and a clinical attack occurs. 

Mitochondria 39% 18-22% 1,700-2,200 Protein secretion, haem synthesis, transport and degradation functions, cellular energy generation (ATP), oxidative phosphorylation, urea synthesis, gluconeogenesis, liponeogenesis, ketogenesis, p-oxidation of fatty acids, citric acid cycle, respiratory chain, etc. 

Porphyrins represent the prosthetic groups of haemo-proteins (haemoglobin, myoglobin, cytochromes, oxygenases, catalases, peroxidases, etc.). The chemical parent compound of the porphyrins is the tetranuclear pyr-rolic dye, porphin. The capacity for haem synthesis is common to almost all cells, but is especially important... 

Fig. 3.2 Diagram showing porphyrin metabolism with haem synthesis in the liver (0.7-1.4 pmol/kg body weight per day = ca. 10-20% of total haem synthesis) (s. tab. 3.3)...

Disorder of haem synthesis Inhibition of hepatic coproporphy-rinogen-oxidase and uroporphyrinogen-decarboxylase can give... 

Primary porphyrias are caused by hereditary enzyme defects in haem synthesis. They can be differentiated clinically into acute and chronic porphyrias as well as pathogenetically into hepatic and erythropoietic porphyrias. Secondary porphyrias are symptomatic porphyrias present in various diseases or caused by poisoning or chemical substances, particularly alcohol. Depending on the preferred manifestation site of the enzyme defect, either in the hepatocytes or erythrocytes (bone marrow), the porphyrias are subdivided into hepatic, erythropoietic and hepatoerythropoietic forms. However, this classification is not always strictly applicable. Based on the course of disease, acute and chronic forms may be differentiated in primary hepatic porphyrias. The acute form is characterized by a congenital reg-... 

ALA synthase can be suppressed by glucose. Due to the short half-life of ALA synthase of 70-80 minutes, inhibition or induction of this enzyme very quickly affects haem synthesis. Haem deficiency due to an enzyme defect causes an increase in 5-aminolaevulinic acid. Free haem is either integrated into various apoproteins or it intervenes as a haem repressor with the nuclear gene chain, which leads to the formation of specific mRNA for ALA synthase. Synthesis and consumption of haem are synchronized precisely. The organism produces some 300 mg haem per day, with only 1% being excreted unused in the urine or faeces. (271, 273, 300, 309) (s. p. 34) (s. tab. 3.3)... 

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