Heme precursors

Acute intermittent porphyria is a dominantly inherited partial deficiency of porphobilinogen deaminase, and causes axonal polyneuropathy. Acute intermittent porphyria is caused by partial deficiency of porphobilinogen deaminase, an enzyme required for heme biosynthesis. Patients may present with acute abdominal pain, rapidly progressive sensorimotor axonal polyneuropathy or psychosis, and have elevated concentrations of the heme precursor 8-amino-levulinic acid in their urine. Symptoms may be precipitated by treatment with barbiturates or other drugs and are suppressed by treatment with hematin [59]. 

Based on the first FAB-MS data, we assumed IV and V-2 to be two isomers with a pyrrolemethanol and a pyrroleninone nucleus, respectively (fig. 8), originating from the condensation of A-DHLNL with an oxidized hydroxylysine residue (fig. 9). The proposed formation of IV is a Knorr-Paal condensation, which has been proposed for the formation of an other pyrrolic cross-link analogous to the heme-precursor porphobilinogen (Scott et al., 1981). In addition, both IV and V-2 had migration speeds comparable to HP (III) in capillary electrophoresis. The presence... 

There are a large number of hereditary or acquired disturbances of porphyrin synthesis, known as porphyrias, some of which can cause severe clinical pictures. Several of these diseases lead to the excretion of heme precursors in feces or urine, giving them a dark red color. Accumulation of porphyrins in the skin can also occur, and exposure to light then causes disfiguring, poorly healing blisters. Neurological disturbances are also common in the porphyrias. 

Acute hereditary porphyrias are disorders of heme synthesis in which overproduction of heme precursors is often accompanied by severe clinical manifestations. Most of the time these diseases remain clinically latent and only occasionally result in acute abdominal and neuropsychiatric symptoms. Occurrence of the symptoms often follows exposure to drugs, such as barbiturates, sulfonamides, estrogens and some local anesthetics (Blanloeil et al. 1989). 

The synthesis and turnover of porphyrins, heme precursors, are important because of the central roles of the heme proteins, hemoglobin, and the cytochromes. Quantitatively, hemoglobin synthesis is a major part of the nitrogen economy in humans. 

Much has been learned from synthetic complexes (Section 17-E-7). The requirements to mimic oxyhemoglobin are the formation of a 5-coordinate heme precursor having a proximal base (imidazol, pyridine, or other) and hindering pathways that would lead to irreversible formation of /i-peroxo dimers. The lifetime of the working models is increased by exclusion of acidic protons and nucleophiles from the 02 binding site and working at low temperatures. 

Cytochrome synthesis was examined in the fat body of adult male B. discoidalis by measuring the synthesis of cytochrome hemes. Heme is synthesized from the condensation of succinate and glycine by aminolevulinic acid synthase to produce aminolevulinic acid (ALA), a specific heme precursor. A developmental pattern exists for the incorporation of [i CjALA into cytohemes of fat body mitochondria with a peak of synthesis between days 4 and 6 of adult age (60). CC ablation eliminates this peak of synthesis for cytohemes a and b CC extract injections return the synthesis of cytohemes a+b to normal levels in CC-ablated cockroaches but have no effects on the synthesis of the c-type hemes for cytochromes c and Cj, The synthesis of cytohemes a+b in response to CC extracts requires a latent period of 24-48 hr to obtain a maximum response and is dose-dependent over a range of 0.01 to 0.08 CC pair (61). The active factor in CC extracts is sensitive to chymotrypsin but not to trypsin. This "cytochromogenic hormone (CGH) is secreted on days 2-3 of adult age in males (62). Since maximal synthesis of cytohemes a+b occurs on day 4, CGH secretion on days 2-3 agrees with the earlier observation that CGH requires about 48 hr to produce its response (61). 

This highly distinctive labeling pattern led Shemin to propose that a heme precursor is formed by the condensation of glycine with an activated succinyl compound. In fact, the first step in the biosynthesis ofporphyrins in mammals is the condensation of glycine and succinyl CoA to form 8-aminolevulinate. 

A number of cLiiiical situations exist that benefit from laboratory testing for heme precursors. These mclude patients with symptoms of acute porphyria, typical cutaneous lesions, and relatives of patients known to have porphyria. 

The clinical features of the porphyrias are insufficiently specific to enable then diagnosis without laboratory investigation. In patients with current symptoms caused by porphyria, it is always possible to demonstrate excessive production of heme precursors. Diagnosis depends on demonstrating specific patterns of overproduction of heme precursors (Table 32-5) and is usually straightforward provided appropriate specimens are examined for the relevant intermediates using adequately sensitive techniques,... 

Felitsyn N, McLeod C, Shroads AL, Stacpoole PW, Notterpek L (2008) The heme precursor delta-aminolevulinate blocks peripheral myelin formation. J Neurochem 106 2068-2079... 

From these structural and chemical features considered necessary to mimic oxyhemoglobin or oxymyoglobin, there are at least two minimum requirements that any realistic models must satisfy (1) formation of a five-coordinate heme precursor having a proximal base (imidazole, pyridine and so on) and (2) limitation of pathways that lead to irreversible oxidation. 

Rittenhouse-Diakun, K., van Leengoed, H., Morgan, J., Hryhorenko, E., Paszkiewicz, G., Whitaker, J.E., and Oseroff, A.R. (1995) The role of transferrin receptor (CD71) in photodynamic therapy of activated and malignant lymphocytes using the heme precursor 8-aminolevulinic acid (ALA), Photochem. Photobiol., 61 523-528. 

Rose, E., A. Lecas, M. Quelquejeu, A. Kossanyi, and B. Boitrel (1998). Synthesis of biomimetic heme precursors. Coord. Chem. Rev. 178-180, 1407-1431. 

Figure 6. The biosynthetic pathway for the production of heme. The enzymes and metabolites are located in the mitochondria (M) and the cytosol (C). Heme negatively regulates ALA synthase at several points, three of which are shown in the figure. Exogenous ALA induces excess formation of heme precursors, including PpIX that can be utilized for photosensitization. (N) nucleus where transcriptional control occurs.

The cellular levels of iron and ferrochelatase are important determinants of PpIX yield under exogenous ALA stimulation. The use of iron chelators is based on the relative inefficiency of ferrochelatase compared to other enzymes, which causes PpIX build-up when heme precursors are produced at an increased rate. In some cancer cell lines lower levels of ferrochelatase have been found than in normal cells and this may contribute to tumor selectivity in certain cancers [197]. In an attempt to further reduce or totally abrogate heme formation, exogenous chelating agents were used to remove iron. It was shown in vitro that iron chelation caused both increased PpIX formation and improved PDT efficacy and in vivo applications in animals and humans have confirmed the concept [191,198,199]. In lymphocytes that express the transferrin receptor (CD71), which is interpreted as an indication of low intracellular iron levels, higher PpIX concentrations were reached under ALA stimulation [200]. In addition, an analysis of iron availability at the molecular level... 

Necessary conditions for synthetic models to mimic oxyhemoglobins are formation of a five-coordinate heme precursor with a proximal base (e.g., imidazole, pyridine), prevention of p-peroxo/p-oxo (M-02-M/M-0-M) dimer formation upon oxygenation (i.e., reversible oxygenation), and exclusion of protons and nucleophiles. Model systems should be easily modified and allow probing of distal and proximal influences. Tetraphenyl-porphyrins (TPP) serve as the basis of numerous model complexes, because they are less susceptible to oxidation... 

Though less than 1% of the total iron in the body is utilized for enzymes and cofactors, the critical nature of these enzymes in such major metabolic pathways as the tricarboxylic acid cycle could easily explain brain effects of iron deficiency. Pollitt and Leibel (1976) also suggest that central catecholamine excess causes some of the behavioral disturbances attributed to iron deficiency. Monoamine oxidase is functionally deranged in iron-deficient rats. Children with iron-deficient anemia have elevated urinary norepinephrine excretion which is normalized within 1 wk after parenteral iron treatment. Potentially toxic excess heme precursors, protoporphyrins, may also mediate the behavioral effects of iron deficiency. 

Metals may impair the metabolism of porphyrins and other heme precursors by direct or indirect compromise of heme pathway enzymes or by reducing the availability of substrates and/or cofactors required for enzyme function. 

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