Emergence of W272C Substitution in Hmg1 in a Triazole-Resistant Isolate of Aspergillus fumigatus from a Chinese Patient with Chronic Cavitary Pulmonary Aspergillosis

Recently, mutations in the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase gene (hmg1) have been identified to be associated with triazole resistance in Aspergillus fumigatus. Here, we describe the first case of the G929C mutation in the hmg1 gene, leading to the W272C amino acid substitution, in a triazole-resistant isolate of A. fumigatus recovered from a chronic cavitary pulmonary aspergillosis patient who failed voriconazole therapy in China.

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Triazole resistant Aspergillus fumigatus in an Israeli patient with Chronic Cavitary Pulmonary Aspergillosis due to a novel E306K Substitution in Hmg1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01089-21 ◽

2021 ◽

Author(s):

Mariana Handelman ◽

Alma Morogovsky ◽

Wei Liu ◽

Ronen Ben-Ami ◽

Nir Osherov

Keyword(s):

Aspergillus Fumigatus ◽

Coenzyme A ◽

Pulmonary Aspergillosis ◽

Hmg Coa Reductase ◽

Therapeutic Challenge ◽

Reductase Gene ◽

Coa Reductase

Triazole resistance in the pathogenic mold Aspergillus fumigatus has increased worldwide, posing a growing therapeutic challenge. Recently, mutations in the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase gene ( hmg1 ) have been associated with triazole resistance. Here, we describe a novel E306K triazole resistance-conferring mutation in the HMG-CoA reductase gene from an Israeli patient with chronic cavitary pulmonary aspergillosis (CCPA).

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A Novel Y319H Substitution in CYP51C Associated with Azole Resistance in Aspergillus flavus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00637-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6615-6619 ◽

Cited By ~ 35

Author(s):

R. A. Paul ◽

S. M. Rudramurthy ◽

J. F. Meis ◽

J. W. Mouton ◽

A. Chakrabarti

Keyword(s):

Amino Acid ◽

Sequence Analysis ◽

Aspergillus Flavus ◽

Amino Acid Substitution ◽

Resistant Isolate ◽

Azole Resistance ◽

Nucleotide Change ◽

Content Type ◽

Susceptibility Status

ABSTRACTThis study aimed to explore any mutation in theCYP51gene conferring azole resistance inAspergillus flavus. Two voriconazole-resistant and 45 voriconazole-susceptible isolates were included in the study. Sequence analysis demonstrated a T1025C nucleotide change inCYP51C, resulting in the Y319H amino acid substitution in one resistant isolate. However, the earlier described T788G mutation inCYP51Cconferring voriconazole resistance inA. flavusisolates was present in all isolates, irrespective of their susceptibility status.

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Malonyl-Coenzyme A Reductase in the Modified 3-Hydroxypropionate Cycle for Autotrophic Carbon Fixation in Archaeal Metallosphaera and Sulfolobus spp.

Journal of Bacteriology ◽

10.1128/jb.00987-06 ◽

2006 ◽

Vol 188 (24) ◽

pp. 8551-8559 ◽

Cited By ~ 68

Author(s):

Birgit Alber ◽

Marc Olinger ◽

Annika Rieder ◽

Daniel Kockelkorn ◽

Björn Jobst ◽

...

Keyword(s):

Amino Acid ◽

Carbon Fixation ◽

Coenzyme A ◽

Reductase Activity ◽

Growth Conditions ◽

Significant Similarity ◽

Semialdehyde Dehydrogenase ◽

Malonyl Coa ◽

Taxonomic Groups ◽

Coa Reductase

ABSTRACT Autotrophic members of the Sulfolobales (Crenarchaeota) contain acetyl-coenzyme A (CoA)/propionyl-CoA carboxylase as the CO2 fixation enzyme and use a modified 3-hydroxypropionate cycle to assimilate CO2 into cell material. In this central metabolic pathway malonyl-CoA, the product of acetyl-CoA carboxylation, is further reduced to 3-hydroxypropionate. Extracts of Metallosphaera sedula contained NADPH-specific malonyl-CoA reductase activity that was 10-fold up-regulated under autotrophic growth conditions. Malonyl-CoA reductase was partially purified and studied. Based on N-terminal amino acid sequencing the corresponding gene was identified in the genome of the closely related crenarchaeum Sulfolobus tokodaii. The Sulfolobus gene was cloned and heterologously expressed in Escherichia coli, and the recombinant protein was purified and studied. The enzyme catalyzes the following reaction: malonyl-CoA + NADPH + H+ → malonate-semialdehyde + CoA + NADP+. In its native state it is associated with small RNA. Its activity was stimulated by Mg2+ and thiols and inactivated by thiol-blocking agents, suggesting the existence of a cysteine adduct in the course of the catalytic cycle. The enzyme was specific for NADPH (Km = 25 μM) and malonyl-CoA (Km = 40 μM). Malonyl-CoA reductase has 38% amino acid sequence identity to aspartate-semialdehyde dehydrogenase, suggesting a common ancestor for both proteins. It does not exhibit any significant similarity with malonyl-CoA reductase from Chloroflexus aurantiacus. This shows that the autotrophic pathway in Chloroflexus and Sulfolobaceae has evolved convergently and that these taxonomic groups have recruited different genes to bring about similar metabolic processes.

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The Promoter of the Rat 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene Contains a Tissue-Specific Estrogen-Responsive Region

Molecular Endocrinology ◽

10.1210/mend.13.8.0333 ◽

1999 ◽

Vol 13 (8) ◽

pp. 1225-1236 ◽

Cited By ~ 20

Author(s):

Luciano Di Croce ◽

Guillermo P. Vicent ◽

Adali Pecci ◽

Giovannella Bruscalupi ◽

Anna Trentalance ◽

...

Keyword(s):

Estrogen Receptor ◽

Cell Lines ◽

Coenzyme A ◽

Cholesterol Metabolism ◽

Hmg Coa Reductase ◽

Tissue Specific ◽

Reductase Gene ◽

Responsive Element ◽

Coa Reductase ◽

Mcf 7

Abstract The isoprenoid metabolic pathway is mainly regulated at the level of conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate, catalyzed by HMG CoA reductase. As estrogens are known to influence cholesterol metabolism, we have explored the potential regulation of the HMG CoA reductase gene promoter by estrogens. The promoter contains an estrogen-responsive element-like sequence at position −93 (termed Red-ERE), which differs from the ERE consensus by one mismatch in each half of the palindrome. A Red-ERE oligonucleotide specifically bound estrogen receptor in vitro and conferred receptor-dependent estrogen responsiveness to a heterologous promoter in all cell lines tested. However, expression of a reporter driven by the rat HMG CoA reductase promoter was induced by estrogen treatment after transient transfection into the breast cancer cell line MCF-7 cells but not in hepatic cell lines expressing estrogen receptor. Estrogen induction in MCF-7 cells was dependent on the Red-ERE and was strongly inhibited by the antiestrogen ICI 164,384. A functional cAMP-responsive element is located immediately upstream of the Red-ERE, but cAMP and estrogens inhibit each other in terms of transactivation of the promoter. Similarly, induction by estrogens was inhibited by micromolar concentrations of cholesterol, likely acting via changes in occupancy of the sterol-responsive element located 70 bp upstream of the Red-ERE. Thus, within its natural context, Red-ERE is able to mediate hormonal regulation of the HMG CoA reductase gene in tissues that respond to estrogens with enhanced cell proliferation, while it is not operative in liver cells. We postulate that this tissue-specific regulation of HMG CoA reductase by estrogens could partially explain the protective effect of estrogens against heart disease.

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Purification, Characterization, and Cloning of a Eubacterial 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, a Key Enzyme Involved in Biosynthesis of Terpenoids

Journal of Bacteriology ◽

10.1128/jb.181.4.1256-1263.1999 ◽

1999 ◽

Vol 181 (4) ◽

pp. 1256-1263 ◽

Cited By ~ 42

Author(s):

Shunji Takahashi ◽

Tomohisa Kuzuyama ◽

Haruo Seto

Keyword(s):

Amino Acid ◽

Coenzyme A ◽

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Gel Filtration ◽

Ph Optimum ◽

Hmg Coa Reductase ◽

Apparent Homogeneity ◽

Key Enzyme ◽

Coa Reductase

ABSTRACT The eubacterial 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34 ) was purified 3,000-fold fromStreptomyces sp. strain CL190 to apparent homogeneity with an overall yield of 2.1%. The purification procedure consisted of (NH4)2SO4 precipitation, heat treatment and anion exchange, hydrophobic interaction, and affinity chromatographies. The molecular mass of the enzyme was estimated to be 41 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 100 to 105 kDa by gel filtration chromatography, suggesting that the enzyme is most likely to be a dimer. The enzyme showed a pH optimum of around 7.2, with apparent Km values of 62 μM for NADPH and 7.7 μM for HMG-CoA. A gene from CL190 responsible for HMG-CoA reductase was cloned by the colony hybridization method with an oligonucleotide probe synthesized on the basis of the N-terminal sequence of the purified enzyme. The amino acid sequence of the CL190 HMG-CoA reductase revealed several limited motifs which were highly conserved and common to the eucaryotic and archaebacterial enzymes. These sequence conservations suggest a strong evolutionary pressure to maintain amino acid residues at specific positions, indicating that the conserved motifs might play important roles in the structural conformation and/or catalytic properties of the enzyme.

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Emergence of Echinocandin Resistance Due to a Point Mutation in the fks1 Gene of Aspergillus fumigatus in a Patient with Chronic Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01277-17 ◽

2017 ◽

Vol 61 (12) ◽

Cited By ~ 29

Author(s):

Cristina Jiménez-Ortigosa ◽

Caroline Moore ◽

David W. Denning ◽

David S. Perlin

Keyword(s):

Aspergillus Fumigatus ◽

Point Mutation ◽

Hot Spot ◽

Pulmonary Aspergillosis ◽

Content Type ◽

First Case ◽

Chronic Pulmonary Aspergillosis ◽

Echinocandin Resistance

ABSTRACT We have identified the first case of an fks1 hot spot 1 point mutation causing echinocandin resistance in a clinical Aspergillus fumigatus isolate recovered from a chronic pulmonary aspergillosis patient with an aspergilloma who first failed azole and polyene therapy and subsequently failed micafungin treatment.

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BadM Is a Transcriptional Repressor and One of Three Regulators That Control Benzoyl Coenzyme A Reductase Gene Expression in Rhodopseudomonas palustris

Journal of Bacteriology ◽

10.1128/jb.01312-06 ◽

2006 ◽

Vol 188 (24) ◽

pp. 8662-8665 ◽

Cited By ~ 20

Author(s):

Caroline M. Peres ◽

Caroline S. Harwood

Keyword(s):

Gene Expression ◽

Coenzyme A ◽

Rhodopseudomonas Palustris ◽

Transcriptional Repressor ◽

Benzoate Degradation ◽

Highly Sensitive ◽

Reductase Gene ◽

Unknown Gene ◽

Coa Reductase ◽

Rate Limiting

ABSTRACT The rate-limiting enzyme of anaerobic benzoate degradation by Rhodopseudomonas palustris, benzoyl coenzyme A (CoA) reductase, is highly sensitive to oxygen, and its synthesis is tightly regulated. We determined that a previously unknown gene in the benzoate gene cluster, badM, encodes a transcriptional repressor of benzoyl-CoA reductase gene expression. BadM controls gene expression from the benzoyl-CoA reductase promoter in concert with two previously described transcriptional activators.

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Emergence of azole resistant-Aspergillus fumigatus infections during STAT3-deficiency

Journal of Medical Microbiology ◽

10.1099/jmm.0.001200 ◽

2020 ◽

Vol 69 (6) ◽

pp. 844-849 ◽

Cited By ~ 1

Author(s):

François Danion ◽

Amélie Duréault ◽

Cécile Gautier ◽

Agathe Senechal ◽

Florence Persat ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Fungal Infections ◽

Allergic Bronchopulmonary Aspergillosis ◽

Point Mutations ◽

Pulmonary Aspergillosis ◽

First Case ◽

High Prevalence ◽

Immune Deficiencies ◽

Transcription 3

Introduction. Signal transducer and activator of transcription 3 (STAT3) deficiency is a rare primary immunodeficiency associated with increased susceptibility to bacterial and fungal infections, notably pulmonary aspergillosis. Aim. We describe the emergence of azole-resistant Aspergillus fumigatus infections in STAT3-deficient patients. Methodology. During a retrospective study of 13 pulmonary aspergillosis cases in STAT3-deficient patients conducted in France, we identified patients infected with azole-resistant A. fumigatus isolates. Results. Two out of the 13 STAT3-deficient patients with aspergillosis had azole-resistant A. fumigatus infection, indicating an unexpectedly high prevalence of resistance. The first patient with STAT3 deficiency presented several flares of allergic bronchopulmonary aspergillosis-like episodes. He was chronically infected with two azole-resistant A. fumigatus isolates (TR34/L98). Despite prolonged antifungal treatment, including caspofungin and amphotericin B, the patient was not able to clear the azole-resistant A. fumigatus. The second patient had chronic cavitary pulmonary aspergillosis (CCPA). The A. fumigatus isolate was initially azole susceptible but harboured three F46Y, M172V and E427K point mutations. Despite prolonged antifungal therapies, lesions worsened and the isolate became resistant to all azoles. Surgery and caspofungin treatments were then required to cure CCPA. Resistance was probably acquired from the environment (TR34/L98) in the first case whereas resistance developed under antifungal treatments in the second case. These infections required long-term antifungal treatments and surgery. Conclusions. The emergence of azole-resistant A. fumigatus infections in STAT3-deficiency dramatically impacts both curative and prophylactic antifungal strategies. Physicians following patients with primary immune-deficiencies should be aware of this emerging problem as it complicates management of the patient.

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Developmental and metabolic regulation of the Drosophila melanogaster 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Molecular and Cellular Biology ◽

10.1128/mcb.8.7.2713 ◽

1988 ◽

Vol 8 (7) ◽

pp. 2713-2721 ◽

Cited By ~ 54

Author(s):

F B Gertler ◽

C Y Chiu ◽

L Richter-Mann ◽

D J Chin

Keyword(s):

Drosophila Melanogaster ◽

Metabolic Regulation ◽

Coenzyme A ◽

Terminal Region ◽

Cdna Clones ◽

Posttranslational Regulation ◽

Hmg Coa Reductase ◽

Reading Frame ◽

Reductase Gene ◽

Coa Reductase

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in Drosophila melanogaster synthesizes mevalonate for the production of nonsterol isoprenoids, which are essential for growth and differentiation. To understand the regulation and developmental role of HMG CoA reductase, we cloned the D. melanogaster HMG CoA reductase gene. The nucleotide sequence of the Drosophila HMG CoA reductase was determined from genomic and cDNA clones. A 2,748-base-pair open reading frame encoded a polypeptide of 916 amino acids (Mr, 98,165) that was similar to the hamster HMG CoA reductase. The C-terminal region had 56% identical residues and the N-terminal region had 7 potential transmembrane domains with 32 to 60% identical residues. In hamster HMG CoA reductase, the membrane regions were essential for posttranslational regulation. Since the Drosophila enzyme is not regulated by sterols, the strong N-terminal similarity was surprising. Two HMG CoA reductase mRNA transcripts, approximately 3.2 and 4 kilobases, were differentially expressed throughout Drosophila development. Mevalonate-fed Schneider cells showed a parallel reduction of both enzyme activity and abundance of the 4-kilobase mRNA transcript.

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