Disease relevance of HMBS

• Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations [1].
• Dual porphyria with mutations in both the UROD and HMBS genes [2].
• Finally a protein comparison study is presented of the Mycobacterium tuberculosis (MTb) HMBS, with the E. coli HMBS [3].
• Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria [4].
• Acute intermittent porphyria (AIP) is a metabolic disease due to a partial deficiency of hydroxymethylbilane synthase (HMBS) in heme biosynthesis [5].

Psychiatry related information on HMBS

• The last few years have seen increasing evidence for the involvement of the UPS in neurodegenerative disorders, including Alzheimer's disease (AD) [6].

High impact information on HMBS

• Lack of effect of pregnancy or hematin therapy on erythrocyte porphobilinogen deaminase activity in acute intermittent porphyria [7].
• We measured the activity of the enzyme porphobilinogen deaminase in red blood cells of 222 persons [8].
• Lymphocyte PBGD determinations also may be of value in determining when to terminate or reinitiate drug treatment [9].
• The diagnostic value of PBGD determinations was shown in a prospective study of a group of patients evaluated because of fever of unknown origin, anemia, or other constitutional symptoms with or without lymphadenopathy or a mediastinal mass [9].
• Patients with malignant lymphoproliferative diseases, ie, chronic lymphocytic leukemia and lymphoma, were found to have higher porphobilinogen deaminase (PBGD) activity in their peripheral lymphocytes than normal control subjects, patients with other malignant neoplasms, and patients with various infectious diseases [9].

Chemical compound and disease context of HMBS

• Acute intermittent porphyria caused by an arginine to histidine substitution (R26H) in the cofactor-binding cleft of porphobilinogen deaminase [10].
• The role of conserved arginine residues in hydroxymethylbilane synthase was investigated by replacing these residues in the enzyme from Escherichia coli with leucine residues by using site-directed mutagenesis [11].
• Porphobilinogen deaminase mutants that cause acute intermittent porphyria have been investigated as recombinant proteins expressed in Escherichia coli, yielding important insight into the mechanism of dipyrromethane cofactor assembly and tetrapyrrole chain polymerization [12].
• An inherited deficiency of porphobilinogen deaminase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] in humans is responsible for the autosomal dominant disease acute intermittent porphyria [13].
• The accumulation of protein deposits in neurons, in vitro proteasome assays and over-expression studies suggest that impairment of the ubiquitin-proteasome system (UPS) may be a common mechanism of pathogenesis in polyglutamine diseases such as Huntington disease and spinocerebellar ataxias (SCAs) [14].

Biological context of HMBS

• Our results define the extent of allelic heterogeneity and the types (41% missense; 59% truncating) and distribution (35% in exons 10, 12, 14) of HMBS mutations, for AIP in the United Kingdom [1].
• Excluding interference of polymorphisms in the primer sites, we assumed the presence of a complete HMBS gene deletion [15].
• PBG-D in control lymphoblasts obeyed Michaelis-Menten kinetics (Vmax 28.7 +/- 1.8 pmol/mg per h, Hill coefficient 0.83 +/- 0.07) [4].
• PBGD also maps to 11q but four recombinants could be identified from ten informative meioses in this family using a PBGD DNA polymorphism [16].
• Dual porphyria in double heterozygotes with porphobilinogen deaminase and uroporphyrinogen decarboxylase deficiencies [17].

Anatomical context of HMBS

• These mutations are likely to be responsible for the decrease in HMBS activity found in both erythrocytes and non-erythroid cell lines (lymphocytes) [18].
• Purified human erythrocyte PBG-D obeyed Michaelis-Menten kinetics (Vmax 249 +/- 36 nmol/mg per h, Km 8.9 +/- 1.5 microM, Hill coefficient 0.93 +/- 0.14) [4].
• Studies of the enzymes of haem biosynthesis in peripheral blood cells showed a dual enzyme deficiency, with reduced activity of both porphobilinogen deaminase, as seen in acute intermittent porphyria, and protoporphyrinogen oxidase, as seen in variegate porphyria [19].
• Two isoforms of PBGD, encoded by two mRNAs differing solely in their 5' end, are known: one is found in all cells and the other is present only in erythroid cells [20].
• Furthermore, Southern blot analysis with somatic cell hybrids showed that the PBGD gene moved to the 14q+chromosome, which confirmed PBGD to be more distal to the centromere than the rck locus [21].

Associations of HMBS with chemical compounds

• During acute attacks delta-aminolevulinic acid and porphobilinogen also increase, suggesting that porphobilinogen deaminase (PBG-D) may be rate limiting [4].
• Studies on the mechanism of hydroxymethylbilane synthase concerning the role of arginine residues in substrate binding [11].
• From the mRNA sequences we could deduce that an additional peptide of 17 amino acid residues at the NH2 terminus of the non-erythropoietic isoform of porphobilinogen deaminase accounts for its higher molecular mass [22].
• We compared the apparent molecular mass of porphobilinogen deaminase from erythropoietic and from non-erythropoietic cells by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and immune-blotting [22].
• Human porphobilinogen deaminase mutations in the investigation of the mechanism of dipyrromethane cofactor assembly and tetrapyrrole formation [12].

Other interactions of HMBS

• Chester porphyria is a distinct type of acute porphyria, which shows a biochemical overlap with acute intermittent and variegate porphyrias and has a dual enzyme deficiency of porphobilinogen deaminase (PBGD) and protoporphyrinogen oxidase [16].
• A coexistent dual enzyme deficiency of PBG-D and URO-D could be confirmed by repeated studies over 10 years [17].
• Even if the deletions include the entire HMBS and H2AFX genes and 1463 bp of the final portion of DPAGT1 gene, our patients had no other symptoms than AIP [15].
• A detailed restriction map of 600 kb of human chromosome band 11q23.3 has been assembled which covers the PBGD, CBL2 and THY1 genes [23].
• ACTB, RPL13A, and HMBS showed significant differences (P<0.02 at least) in expressions between malignant and nonmalignant pairs [24].

Analytical, diagnostic and therapeutic context of HMBS

• Several crystallographic structures of HMBS have been previously determined, most recently including by time-resolved Laue protein crystallography of the Lys59Gln mutant form with reaction initiation undertaken by use of a flow cell carrying the substrate PBG [3].
• Novel mutation and polymorphisms of the HMBS gene detected by denaturing HPLC [25].
• Reporter gene and electrophoretic mobility shift assays show that the G nucleotide at position -154, the most 5' of several transcription-initiation sites in the ubiquitous HMBS promoter, which lies immediately 3' to a transcription-factor IIB binding motif, is essential for normal transcription [26].
• The hydroxymethylbilane synthase (HMBS) mRNAs from 44 control individuals and 30 patients suffering from acute intermittent porphyria (AIP), were screened for length differences by reverse transcriptase polymerase chain reaction (RT-PCR) and any abnormalities were characterized by direct sequencing [27].
• We studied the gene mutation in two unrelated AIP families in the San-in district, a local area of Western Japan. The overlapping 6 fragments of the HMBS gene, amplified by the reverse transcript-polymerase chain reaction, were analyzed by the single-strand conformation polymorphism with silver staining technique [28].

References