Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants, K132N and V215E, with different phenotypic association with acute intermittent porphyria

Bustad, Helene J.; Vorland, Marta; Rønneseth, Eva; Sandberg, Sverre; Martı́nez, Aurora; Toska, Karen

doi:10.1042/bsr20130045

Cited by 21 publications

(45 citation statements)

References 48 publications

(82 reference statements)

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“…Previous studies experimentally characterized two novel mutations by comparing them with wild-type (wt) HMBS (Bustad et al, 2013). Our collected clinical data show that patients with mutation R116W and R173W have severe clinical symptoms, which is consistent with previous study that R116W mutation leads to the protein defection in conformational stability while R173W impacts both enzyme kinetics and conformational stability (Bustad et al, 2013). In the residue interaction network of 5M6R and 5M7F, R173 interacts with many other residues, including S146, I166, G168, N169, K176, L177, I186, and L188.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the collected mutation pattern and clinical information, we analyzed the relationship between genotypes and phenotypes. Previous research has made the conformational stability and activity analysis of several HMBS mutations, they interpreted the molecular mechanisms of HMBS mutations and inferred the connection between genotypes and phenotypes to certain extent (Bustad et al, 2013). By mapping the mutations to the protein crystal structure and conducting the residues interaction analysis, we have obtained more comprehensive view about how the mutations affect the protein function.…”

Section: Discussionmentioning

confidence: 99%

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Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria

Jia

Yue

et al. 2019

Front. Pharmacol.

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The rare autosomal dominant disorder acute intermittent porphyria (AIP) is caused by the deficient activity of hydroxymethylbilane synthase (HMBS). The symptoms of AIP are acute neurovisceral attacks which are induced by the dysfunction of heme biosynthesis. To better interpret the underlying mechanism of clinical phenotypes, we collected 117 HMBS gene mutations from reported individuals with AIP and evaluated the mutations’ impacts on the corresponding protein structure and function. We found that several mutations with most severe clinical symptoms are located at dipyromethane cofactor (DPM) binding domain of HMBS. Mutations on these residues likely significantly influence the catalytic reaction. To infer new pathogenic mutations, we evaluated the pathogenicity for all the possible missense mutations of HMBS gene with different bioinformatic prediction algorithms, and identified 34 mutations with serious pathogenicity and low allele frequency. In addition, we found that gene PPARA may also play an important role in the mechanisms of AIP attacks. Our analysis about the distribution frequencies of the 23 variations revealed different distribution patterns among eight ethnic populations, which could help to explain the genetic basis that may contribute to population disparities in AIP prevalence. Our systematic analysis provides a better understanding for this disease and helps for the diagnosis and treatment of AIP.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria

Jia

Yue

et al. 2019

Front. Pharmacol.

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“…The bulky arginine moiety in the mutant may disrupt the docking or covalent binding of the cofactor to the enzyme, while a charge switch in the p.Lys98Glu mutant has no such effect. Several other mutants (Arg149Gln, Arg173Gln38 and Arg116Trp)39 are also reported to result in the expression of apoenzyme. It is suggested that the disrupted interaction of these residues with the cofactor likely prevents successful docking of hydroxymethylbilane, the DPM precursor, in the active site of the apoenzyme.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

et al. 2016

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“…The mechanism of this phenomenon is ill-defined. 23,25 Moreover, a drug-responsive sequence in the ALAS1 gene mediates a direct transcriptional activation via drugs such as barbiturates, hydantoins, and metyrapone. [26][27][28][29] Glucose activation of peroxisome proliferator-activated receptor g-coactivator 1a prevents transcription of ALAS1.…”

Section: August 2019mentioning

confidence: 99%

Clinical Guide and Update on Porphyrias

Stölzel¹,

Doss²,

Schuppan³

2019

Gastroenterology

123

158

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Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An a-melanocytestimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or Xlinked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.

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Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants, K132N and V215E, with different phenotypic association with acute intermittent porphyria

Cited by 21 publications

References 48 publications

Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria

Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

Clinical Guide and Update on Porphyrias

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