The Aspergillus fumigatus Damage Resistance Protein Family Coordinately Regulates Ergosterol Biosynthesis and Azole Susceptibility

MBio
Jinxing SongLing Lu

Abstract

Ergosterol is a major and specific component of the fungal plasma membrane, and thus, the cytochrome P450 enzymes (Erg proteins) that catalyze ergosterol synthesis have been selected as valuable targets of azole antifungals. However, the opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in the cytochrome P450 enzyme Cyp51 (Erg11). In this study, we demonstrate that a cytochrome b5-like heme-binding damage resistance protein (Dap) family, comprised of DapA, DapB, and DapC, coordinately regulates the functionality of cytochrome P450 enzymes Erg5 and Erg11 and oppositely affects susceptibility to azoles. The expression of all three genes is induced in an azole concentration-dependent way, and the decreased susceptibility to azoles requires DapA stabilization of cytochrome P450 protein activity. In contrast, overexpression of DapB and DapC causes dysfunction of Erg5 and Erg11, resulting in abnormal accumulation of sterol intermediates and further accentuating the sensitivity of ΔdapA strains to azoles. The results of exogenous-hemin rescue and heme-binding-site mutagenesis experiments demonstrate that the heme binding of DapA contributes the decreased azole susceptib...Continue Reading

References

Feb 28, 1996·JAMA : the Journal of the American Medical Association·P A NuttingS Holcomb
Jun 20, 1998·Clinical Microbiology Reviews·T C WhiteR A Bowden
Mar 6, 1999·Current Opinion in Microbiology·N H Georgopapadakou
Dec 4, 2001·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·S AsciogluUNKNOWN Mycoses Study Group of the National Institute of Allergy and Infectious Diseases
Jul 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·C MoM Bard
Feb 1, 2003·Pharmacology & Therapeutics·John B Schenkman, Ingela Jansson
May 15, 2004·Bioorganic & Medicinal Chemistry·Reena GollapudySudhir A Kulkarni
Jun 19, 2004·Molecular Membrane Biology·Alex J Laude, Ian A Prior
Sep 19, 2006·Biochimica Et Biophysica Acta·Frank HannemannRita Bernhardt
Oct 13, 2006·International Journal of Antimicrobial Agents·Susan J HowardDavid W Denning
Feb 6, 2007·Cell Metabolism·Adam L HughesPeter J Espenshade
Nov 23, 2007·Biochemistry·Alisha M ThompsonTheodore R Holman
Jul 28, 2010·Antimicrobial Agents and Chemotherapy·Andrew G S WarrilowDiane E Kelly
Nov 18, 2010·Biochimica Et Biophysica Acta·Sebastien DupontPatrick Gervais
Aug 16, 2012·Proceedings of the National Academy of Sciences of the United States of America·James Peter SáenzKai Simons
Nov 19, 2013·Fungal Genetics and Biology : FG & B·Hechun JiangLing Lu
Jan 1, 2014·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·M C Arendrup
Aug 7, 2014·MBio·Robert ZarnowskiDavid R Andes
Oct 4, 2014·Science·Luis CaspetaJens Nielsen
Jan 3, 2015·Fungal Genetics and Biology : FG & B·Fei-fei LiuLing Lu
Jun 21, 2015·Fungal Genetics and Biology : FG & B·Eveline SneldersWillem J G Melchers

❮ Previous
Next ❯

Citations

Feb 9, 2017·Frontiers in Microbiology·Liliana ScorzoniAna M Fusco-Almeida
Jul 16, 2019·Fungal biology and biotechnology·Andrew S UrquhartAlexander Idnurm
Aug 29, 2019·Journal of Medical Microbiology·Ahmad AjdidiKevin Kavanagh
Aug 9, 2020·Molecular Microbiology·Jinxing SongRongpeng Li
May 10, 2019·Frontiers in Microbiology·Jingxiang ZhangYuanying Jiang
May 27, 2021·Studies in Mycology·A ArastehfarM Hoenigl
Aug 23, 2021·Chinese Journal of Natural Medicines·Fu-Juan SunMing-Hua Yang
Sep 16, 2021·Applied and Environmental Microbiology·Pengfei ZhaiJinxing Song

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
fluorescence microscopy

Software Mentioned

TMHMM
Ensembl Genome Browser

Related Concepts

Related Feeds

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Aspergillosis

Aspergillosis is the name given to a wide variety of diseases caused by infection by fungi of the genus Aspergillus. Aspergillosis occurs in chronic or acute forms which are clinically very distinct. Most cases of acute aspergillosis occur in patients with severely compromised immune systems. Chronic colonization or infection can cause complications in people with underlying respiratory illnesses. Discover the latest research on aspergillosis here.

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.

Aspergillosis (ASM)

Aspergillosis is the name given to a wide variety of diseases caused by infection by fungi of the genus Aspergillus. Aspergillosis occurs in chronic or acute forms which are clinically very distinct. Most cases of acute aspergillosis occur in patients with severely compromised immune systems. Chronic colonization or infection can cause complications in people with underlying respiratory illnesses. Discover the latest research on aspergillosis here.

Candidiasis

Candidiasis is a common fungal infection caused by Candida and it can affect many parts for the body including mucosal membranes as well as the gastrointestinal, urinary, and respiratory tracts. Here is the latest research.

Candidiasis (ASM)

Candidiasis is a common fungal infection caused by Candida and it can affect many parts for the body including mucosal membranes as well as the gastrointestinal, urinary, and respiratory tracts. Here is the latest research.

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.