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Gene Review

ALAD  -  aminolevulinate dehydratase

Homo sapiens

Synonyms: ALADH, Delta-aminolevulinic acid dehydratase, PBGS, Porphobilinogen synthase
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Disease relevance of ALAD

  • Cloning and expression of the defective genes for delta-aminolevulinate dehydratase (ALAD) from a patient with inherited ALAD deficiency porphyria (ADP) were carried out [1].
  • Cloning of cDNAs for the defective ALAD were performed using Epstein-Barr virus (EBV)-transformed lymphoblastoid cells of the proband, and nucleotide sequences of cloned cDNA were determined [2].
  • In order to promote health and to minimize the toxicity of lead exposure more effectively, the nutritional management of iron in Korean workers should take both their ALAD genotypes and occupational lead exposures into account [3].
  • We report the relations among ALAD and VDR genotypes, three lead dose measures, and blood pressure and hypertension status in 798 Korean lead workers and 135 controls without occupational exposure to lead [4].
  • OBJECTIVE: The relationship between polymorphisms of ALAD and VDR genes and individual susceptibility of lead poisoning was investigated in children highly-exposed to lead [5].

Psychiatry related information on ALAD


High impact information on ALAD

  • Cloning of cDNAs for the defective ALAD were performed from EBV-transformed lymphoblastoid cells of the proband, and nucleotide sequences were determined [1].
  • These data thus define the separate point mutations in each ALAD allele, as well as the altered properties of the two enzymic proteins encoded by the mutant genes in a patient with ADP [1].
  • The almost complete inhibition of porphobilinogen synthase in erythrocytes was abolished and the excretion of 5-aminolevulinate decreased to within or slightly above the reference range [8].
  • The allosteric magnesium, present in most PBGS, has a binding site in the octamer but not in the hexamer [9].
  • The unprecedented structural rearrangement reported here relates to the allosteric regulation of PBGS and suggests that alternative PBGS oligomers may function in a magnesium-dependent regulation of tetrapyrrole biosynthesis in plants and some bacteria [9].

Chemical compound and disease context of ALAD

  • Comparison of the crystal structures for E. coli PBGS inactivated by 4-OSA versus 4,7-DOSA shows significant variation in the half of the inhibitor that mimics the second substrate molecule (A-side ALA) [10].
  • Succinylacetone is produced in large amounts by patients suffering from the hereditary disease type I tyrosinaemia and its potent inhibition of ALAD also has implications for the pathology of this disease [11].
  • The last two parameters (ZPP and ALAD) are statistically related to serum aluminum concentration (Al-S), but only the correlation between Al-S and ALAD remains statistically significant after standardization for the degree of renal insufficiency (expressed in terms of urea level) [12].
  • These results suggest that ALAD assay followed by the EDTA mobilization test is as effective in CAPD patients as in NRF subjects to diagnose and to treat chronic abstruse lead poisoning [13].
  • delta-Aminolevulinic acid dehydratase deficiency porphyria (ALAD porphyria, ADP) with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a 69-year-old woman is reported [14].

Biological context of ALAD

  • The second enzyme in the heme biosynthetic pathway, delta-aminolevulinate dehydratase (ALAD), is a homooctameric protein encoded by a gene localized to human chromosome 9q34 [15].
  • The overall prevalence of the ALAD 1-2/2-2 genotype was 9.3%, which was associated with lower log ZPP (p < 0.001) and higher Hb (p = 0.014) levels [3].
  • In contrast to VDR, ALAD genotype was not associated with the blood pressure measures and did not modify associations of the lead dose measures with any of the blood pressure measures [4].
  • The current data confirm past observations that the ALAD gene modifies the toxicokinetics of lead and also provides new evidence that the VDR gene does so as well [16].
  • These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure [17].

Anatomical context of ALAD

  • These data thus demonstrate that the proband was associated with 2 novel molecular defects of the ALAD gene, 1 in each allele, and account for the extremely low ALAD activity in his erythrocytes ( approximately 1% of normal) [2].
  • The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% CI), 0.60-6.3] [17].
  • In conclusion, VDR and/or ALAD genotypes modified associations between all the lead biomarkers, except patella lead, and the renal outcomes [18].
  • Expression of ALAD cDNA in CHO cells revealed that K59N cDNA produced a protein with normal ALAD activity, while G133R and K59N/G133R cDNA produced proteins with 8% and 16% ALAD activity, respectively, compared with that expressed by the wild type cDNA [19].
  • The results suggest that ALAD and PBGD are exclusively plastid enzymes [20].

Associations of ALAD with chemical compounds

  • Among older workers (age > or = median of 40.6 years), ALAD genotype modified associations between lead dose and uric acid levels [21].
  • Additionally, the mutant ALAD cDNA which encodes F12L substitution produced an aberrant migration pattern in polyacrylamide gel electrophoresis under denaturing conditions [22].
  • ALAD is a cytoplasmic enzyme that catalyzes the second step of the heme biosynthesis pathway, that is, the condensation of two molecules of delta-aminolevulinic acid into porphobilinogen [23].
  • Limited evidence of effect modification by ALAD genotype was observed; higher blood lead levels were associated with higher calculated creatinine clearance among participants with the ALAD(1-2) genotype [18].
  • A tissue-specific inhibition of ALAD occurs in the kidney after treatment of rats with indium [24].

Physical interactions of ALAD

  • Here we compare the sensitivity and efficiency of DNA polymorphism detection in the delta-aminolevulinate dehydratase (ALAD) gene encoding the principal lead-binding protein in humans by means of DHPLC and direct DNA sequencing of polymerase chain reaction amplicons [25].

Other interactions of ALAD

  • Distribution of ACP1, AK1 and ALAD polymorphisms in northern Portugal [26].
  • Maximum activities of delta-aminolevulinic acid synthase (ALAS), ALA dehydratase (ALAD), and 14C-ALA incorporation into heme were achieved in normal marrow CFUE after 8 days of culture, whereas heme oxygenase progressively decreased to low levels of activity during the same period [27].
  • No clear effect modification of the relations between the lead biomarkers and hematopoietic outcomes studied was caused by ALAD or VDR genotype [28].
  • Linkage analysis was carried out for markers on chromosome 9, following up a hint of ALADH-ORM linkage in part of the material [29].
  • After acute treatment of rats with lead, no effects on ALAD or UROS and mild, transitory effects on ALAS and ferrochelatase are observed [24].

Analytical, diagnostic and therapeutic context of ALAD

  • We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure [17].
  • There is also some suggestion that aluminum could be responsible for the decreased erythrocyte ALAD activity observed in patients on chronic hemodialysis [23].
  • Though activated d- aminolevulinic acid dehydratase (ALAD) activities in BMW group did not show any significant change when compared to control group but activated / non activated erythrocyte - ALAD activities in BMW group showed a significant increase [30].
  • Expression levels of PfALAD in P. falciparum, based on Western blot analysis, immunoelectron microscopy, and EDTA-resistant enzyme activity assay reveals that it may account for about 10% of the total ALAD activity in the parasite, the rest being accounted for by the host enzyme imported by the parasite [31].
  • A modified B. japonicum ALA dehydratase, ALAD*, was constructed by site-directed mutagenesis of hemB in which three proximal amino acids conserved in plant dehydratases were changed to cysteine residues as is found in the Zn(2+)-dependent enzyme of animals [32].


  1. Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria. Ishida, N., Fujita, H., Fukuda, Y., Noguchi, T., Doss, M., Kappas, A., Sassa, S. J. Clin. Invest. (1992) [Pubmed]
  2. Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria. Akagi, R., Shimizu, R., Furuyama, K., Doss, M.O., Sassa, S. Hepatology (2000) [Pubmed]
  3. The protective effect of delta-aminolevulinic acid dehydratase 1-2 and 2-2 isozymes against blood lead with higher hematologic parameters. Kim, H.S., Lee, S.S., Lee, G.S., Hwangbo, Y., Ahn, K.D., Lee, B.K. Environ. Health Perspect. (2004) [Pubmed]
  4. Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes. Lee, B.K., Lee, G.S., Stewart, W.F., Ahn, K.D., Simon, D., Kelsey, K.T., Todd, A.C., Schwartz, B.S. Environ. Health Perspect. (2001) [Pubmed]
  5. A molecular epidemiological study of childhood lead poisoning in lead-polluted environment. Zheng, Y., Leng, S., Song, W., Wang, Y., Niu, Y., Zhang, W., Yan, H., Liu, Y., Huang, Q., Wu, Y. Zhonghua Liu Xing Bing Xue Za Zhi (2002) [Pubmed]
  6. In vivo study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man. Telisman, S., Prpić-Majić, D., Kezić, S. Scandinavian journal of work, environment & health. (1984) [Pubmed]
  7. Increased blood lead levels in mentally retarded children in Greece. Youroukos, S., Lyberatos, C., Philippidou, A., Gardikas, C., Tsomi, A. Arch. Environ. Health (1978) [Pubmed]
  8. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lindstedt, S., Holme, E., Lock, E.A., Hjalmarson, O., Strandvik, B. Lancet (1992) [Pubmed]
  9. Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase. Breinig, S., Kervinen, J., Stith, L., Wasson, A.S., Fairman, R., Wlodawer, A., Zdanov, A., Jaffe, E.K. Nat. Struct. Biol. (2003) [Pubmed]
  10. Species-specific inhibition of porphobilinogen synthase by 4-oxosebacic acid. Jaffe, E.K., Kervinen, J., Martins, J., Stauffer, F., Neier, R., Wlodawer, A., Zdanov, A. J. Biol. Chem. (2002) [Pubmed]
  11. The x-ray structure of yeast 5-aminolaevulinic acid dehydratase complexed with substrate and three inhibitors. Erskine, P.T., Newbold, R., Brindley, A.A., Wood, S.P., Shoolingin-Jordan, P.M., Warren, M.J., Cooper, J.B. J. Mol. Biol. (2001) [Pubmed]
  12. Effect of aluminum on porphyrin metabolism in hemodialyzed patients. Buchet, J.P., Lauwerys, R., Hassoun, A., Dratwa, M., Wens, R., Collart, F., Tielemans, C. Nephron (1987) [Pubmed]
  13. Diagnosis and treatment of chronic lead poisoning in CAPD patients. Kessler, M., Durand, P.Y., Hestin, D., Gamberoni, J., Chanliau, J. Advances in peritoneal dialysis. Conference on Peritoneal Dialysis. (1993) [Pubmed]
  14. delta-Aminolevulinic acid dehydratase deficiency porphyria (ADP) with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a 69-year-old woman. Muraoka, A., Suehiro, I., Fujii, M., Murakami, K. The Kobe journal of medical sciences. (1995) [Pubmed]
  15. Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning. Wetmur, J.G., Kaya, A.H., Plewinska, M., Desnick, R.J. Am. J. Hum. Genet. (1991) [Pubmed]
  16. Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta]-aminolevulinic acid dehydratase genes. Schwartz, B.S., Lee, B.K., Lee, G.S., Stewart, W.F., Simon, D., Kelsey, K., Todd, A.C. Environ. Health Perspect. (2000) [Pubmed]
  17. Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes. Kamel, F., Umbach, D.M., Lehman, T.A., Park, L.P., Munsat, T.L., Shefner, J.M., Sandler, D.P., Hu, H., Taylor, J.A. Environ. Health Perspect. (2003) [Pubmed]
  18. Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers. Weaver, V.M., Lee, B.K., Todd, A.C., Ahn, K.D., Shi, W., Jaar, B.G., Kelsey, K.T., Lustberg, M.E., Silbergeld, E.K., Parsons, P.J., Wen, J., Schwartz, B.S. Environmental research. (2006) [Pubmed]
  19. Molecular analysis of delta-aminolevulinate dehydratase deficiency in a patient with an unusual late-onset porphyria. Akagi, R., Nishitani, C., Harigae, H., Horie, Y., Garbaczewski, L., Hassoun, A., Mercelis, R., Verstraeten, L., Sassa, S. Blood (2000) [Pubmed]
  20. Subcellular localization of two porphyrin-synthesis enzymes in Pisum sativum (pea) and Arum (cuckoo-pint) species. Smith, A.G. Biochem. J. (1988) [Pubmed]
  21. Associations of uric acid with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers. Weaver, V.M., Schwartz, B.S., Jaar, B.G., Ahn, K.D., Todd, A.C., Lee, S.S., Kelsey, K.T., Silbergeld, E.K., Lustberg, M.E., Parsons, P.J., Wen, J., Lee, B.K. Environ. Health Perspect. (2005) [Pubmed]
  22. A novel mutation of delta-aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity. Akagi, R., Yasui, Y., Harper, P., Sassa, S. Br. J. Haematol. (1999) [Pubmed]
  23. Metal-induced alterations of delta-aminolevulinic acid dehydratase. Bernard, A., Lauwerys, R. Ann. N. Y. Acad. Sci. (1987) [Pubmed]
  24. Alterations in renal heme biosynthesis during metal nephrotoxicity. Oskarsson, A., Fowler, B.A. Ann. N. Y. Acad. Sci. (1987) [Pubmed]
  25. Detection of novel ALAD gene polymorphisms using denaturing high-performance liquid chromatography. Niu, T., Seielstad, M., Zeng, X., Apffel, A., Li, G., Hahnenberger, K., Xu, X. Hum. Biol. (2001) [Pubmed]
  26. Distribution of ACP1, AK1 and ALAD polymorphisms in northern Portugal. Amorim, A., Rocha, J., Santos, M.T. Gene geography : a computerized bulletin on human gene frequencies. (1994) [Pubmed]
  27. Regulation of heme metabolism in normal and sideroblastic bone marrow cells in culture. Ibraham, N.G., Lutton, J.D., Hoffman, R., Levere, R.D. J. Lab. Clin. Med. (1985) [Pubmed]
  28. Associations of lead biomarkers and delta-aminolevulinic acid dehydratase and vitamin D receptor genotypes with hematopoietic outcomes in Korean lead workers. Lee, S.S., Lee, B.K., Lee, G.S., Stewart, W.F., Simon, D., Kelsey, K., Todd, A.C., Schwartz, B.S. Scandinavian journal of work, environment & health. (2001) [Pubmed]
  29. delta-Aminolevulinatedehydrase: synteny with ABO-AK1-ORM (and assignment to chromosome 9). Eiberg, H., Mohr, J., Nielsen, L.S. Clin. Genet. (1983) [Pubmed]
  30. Effect of Lead (Pb) Exposure on the Activity of Superoxide Dismutase and Catalase in Battery Manufacturing Workers (BMW) of Western Maharashtra (India) with Reference to Heme biosynthesis. Patil, A.J., Bhagwat, V.R., Patil, J.A., Dongre, N.N., Ambekar, J.G., Jailkhani, R., Das, K.K. International journal of environmental research and public health (2006) [Pubmed]
  31. Delta-aminolevulinic acid dehydratase from Plasmodium falciparum: indigenous versus imported. Dhanasekaran, S., Chandra, N.R., Chandrasekhar Sagar, B.K., Rangarajan, P.N., Padmanaban, G. J. Biol. Chem. (2004) [Pubmed]
  32. A mutant Bradyrhizobium japonicum delta-aminolevulinic acid dehydratase with an altered metal requirement functions in situ for tetrapyrrole synthesis in soybean root nodules. Chauhan, S., O'Brian, M.R. J. Biol. Chem. (1995) [Pubmed]
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