Disease relevance of Succinylacetone

• Hereditary tyrosinemia. Formation of succinylacetone-amino acid adducts [1].
• Augmentation of hematoporphyrin uptake and in vitro-growth inhibition of L1210 leukemia cells by succinylacetone [2].
• We report here that fahA, the gene encoding Fah in the fungus Aspergillus nidulans, encodes a polypeptide showing 47.1% identity to its human homologue, fahA disruption results in secretion of succinylacetone (a diagnostic compound for human type I tyrosinaemia) and phenylalanine toxicity [3].
• Proteins suppressed in anoxia were also suppressed during aerobic incubation with Co2+ or Ni2+ but this was not relieved by 4,6-dioxoheptanoic acid [4].
• These and additional data stemming from inhibition of heme synthesis with succinylacetone or from iron overload suggest that highly efficient utilization of iron in mitochondrial heme synthesis during normal erythropoiesis alters the regulation of iron metabolism via the IRE/IRP system [5].

High impact information on Succinylacetone

• Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone [6].
• Increased levels of the diagnostic metabolite succinylacetone in the urine of the Fah(6287SB) and Fah(5961SB) mutants indicate that these mutations cause a decrease in Fah enzymatic activity [7].
• SA was shown to inhibit in vitro the overall DNA-ligase activity present in normal cell extracts [8].
• These results suggest that accumulation of SA reduces the overall ligase activity in HT1 cells and indicate that metabolism errors may play a role in regulating enzymatic activities involved in DNA replication and repair [8].
• In this pilot project, FAH was measured first, and, if necessary, succinylacetone was determined as the complementary test [9].

Chemical compound and disease context of Succinylacetone

• In this study, succinylacetone, a powerful inhibitor of delta-aminolevulinic acid dehydrase was used to block heme synthesis and to study the effects of heme depletion on the dimethylsulfoxide (DMSO)-mediated induction of the heme pathway enzymes in Friend virus-transformed erythroleukemia cells [10].
• Succinyl acetone plus methotrexate as graft-versus-host disease prophylaxis in DLA-haploidentical canine littermate marrow grafts [11].
• Iron mobilization by succinylacetone methyl ester in rats. A model study for hereditary tyrosinemia and porphyrias characterized by 5-aminolevulinic acid overload [12].
• To investigate effects of ALA independent of porphyrin accumulation we treated rats with the methyl ester of succinylacetone, an inhibitor of 5-aminolevulinic acid dehydratase that accumulates in the porphyric-like syndrome hereditary tyrosinemia [12].
• 2. Intraperitoneal injection of succinylacetone for 3 consecutive days into adult male Sprague-Dawley rats resulted in succinylacetone plasma concentration of 3 mmol/l. This concentration was associated with glucosuria, aminoaciduria, polyuria, reduced renal phosphate reabsorption and normal creatinine clearance [13].

Biological context of Succinylacetone

• Other tyrosine metabolites, maleylacetoacetate and succinylacetone, had no antiproliferative effects and induced only very low levels of apoptosis [14].
• Inhibitors such as imidazole or succinylacetone, which inhibit haemoglobin synthesis but not commitment to terminal cell division, did not suppress Bcl-XL induction in DMSO-induced cells [15].
• Blocking heme synthesis with succinyl acetone completely inhibited heterodimer formation, although biogenesis of gp65 and p22(phox) was unaffected [16].
• Succinylacetone is a seven-carbon organic ketoacid that we have previously shown to inhibit tumor allograft rejection as well as the primary antibody response to sheep erythrocytes in rats [17].
• Succinylacetone appears to be unique by inducing a number of conformational changes in loops covering the active site, which may be important for understanding the co-operative properties of ALAD enzymes [18].

Anatomical context of Succinylacetone

• Distribution of iron in reticulocytes after inhibition of heme synthesis with succinylacetone: examination of the intermediates involved in iron metabolism [19].
• When succinylacetone is used to inhibit Belgrade heme synthesis, iron from diferric transferrin does not accumulate in the stromal fraction that contains mitochondria, nor does 59Fe accumulate in the nonheme cytosolic fraction [20].
• Succinylacetone inhibits heme synthesis, leading to nonheme iron accumulation in mitochondria and cytosol of normal reticulocytes [20].
• To confirm this observation and determine whether succinylacetone would interfere with bone marrow engraftment, lethally irradiated adult Wistar-Furth rats were reconstituted with syngeneic or totally allogeneic Fisher 344 lymphohemopoietic cells consisting of equal numbers of bone marrow and spleen cells [17].
• Cytotoxicity typing of peripheral lymphocytes demonstrated greater than 90% donor-type lymphocytes persisting in the succinylacetone-treated recipients as long as 255 days post-transplantation [17].

Associations of Succinylacetone with other chemical compounds

• When cellular heme content was decreased by inhibiting heme synthesis with succinylacetone (an inhibitor of 5-aminolevulinic acid dehydratase), or by depriving cells of iron with deferoxamine, an increase in HeLa cell transferrin receptor number was seen [21].
• A thiol-blocking reagent, N-ethylmaleimide, as well as myeloperoxidase inhibitors (succinyl acetone and azide), blocked formation of fluorescent acridine-piperidine [22].
• In the homogentisate-treated Fah-/- Hpd-/- mice, massive amounts of succinylacetone were excreted into the urine, regardless of treatment with inhibitors [23].
• The structures of 5-aminolaevulinic acid dehydratase (ALAD) complexed with substrate (5-aminolaevulinic acid) and three inhibitors: laevulinic acid, succinylacetone and 4-keto-5-aminolaevulinic acid, have been solved at high resolution [18].
• Ascorbate also diminishes etoposide-induced topo II-DNA complex formation in myeloperoxidase-rich HL60 cells (but not in HL60 cells with myeloperoxidase activity depleted by pretreatment with succinyl acetone) [24].

Gene context of Succinylacetone

• The MARE binding activity of Bach1 in K562 and MEL cells increased upon SA treatment, and the increase was diminished by the treatment with hemin [25].
• SA had no effect on TfR expression in Fw cells [26].
• Treatment of HLE/2E1 cells with succinylacetone (SA), a potent inhibitor of delta-aminolevulinate dehydratase and thereby heme synthesis, resulted in a further increase in ALAS-N mRNA but a decrease in HO-1 mRNA levels [27].
• The addition of SA did not alter the c-myc response of ECFC to EP [28].
• In short-term (1-2 hours) incubation, SA inhibited 59Fe incorporation from transferrin into heme, whereas total cellular 59Fe uptake was increased [26].

Analytical, diagnostic and therapeutic context of Succinylacetone

• No chronic or late developing acute GVHD was observed even though the animals received succinylacetone as the sole immunosuppressant for only 28 days after transplantation [17].
• Furthermore, hemopoietic reconstitution in recipients of syngeneic cells was essentially identical between the control group and the group treated with succinylacetone [17].
• Immunosuppression by succinylacetone. II. Prevention of graft-vs-host disease [17].
• Furthermore, chromatin immunoprecipitation experiments revealed that Bach1 bound to the MARE of HS2 increased by the treatment of MEL cells with SA, and this was cancelled by hemin [25].
• Four dogs were given 9.2 Gy total-body irradiation and autologous marrow transplants along with continuous i.v. infusion of succinyl acetone at 50, 100, 200, or 400 mg/kg/day for 21 days, and all four had rapid, sustained hematopoietic engraftment [29].

References