An Unconventional Hexacoordinated Flavohemoglobin from Mycobacterium tuberculosis

被引:15
|
作者
Gupta, Sanjay [1 ]
Pawaria, Sudesh [1 ]
Lu, Changyuan [2 ]
Hade, Mangesh Dattu [1 ]
Singh, Chaahat [1 ]
Yeh, Syun-Ru [2 ]
Dikshit, Kanak L. [1 ]
机构
[1] CSIR, Inst Microbial Technol, Chandigarh 160036, India
[2] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA
基金
美国国家科学基金会;
关键词
D-LACTATE DEHYDROGENASE; ESCHERICHIA-COLI FLAVOHEMOGLOBIN; RESONANCE RAMAN-SPECTROSCOPY; NITRIC-OXIDE; BACTERIAL HEMOGLOBINS; CAMPYLOBACTER-JEJUNI; NITROSATIVE STRESS; RESPIRATORY ENZYME; PURIFICATION; ADAPTATION;
D O I
10.1074/jbc.M111.329920
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Being an obligate aerobe, Mycobacterium tuberculosis faces a number of energetic challenges when it encounters hypoxia and environmental stress during intracellular infection. Consequently, it has evolved innovative strategies to cope with these unfavorable conditions. Here, we report a novel flavohemoglobin (MtbFHb) from M. tuberculosis that exhibits unique features within its heme and reductase domains distinct from conventional FHbs, including the absence of the characteristic hydrogen bonding interactions within the proximal heme pocket and mutations in the FAD and NADH binding regions of the reductase domain. In contrast to conventional FHbs, it has a hexacoordinate low-spin heme with a proximal histidine ligand lacking imidazolate character and a distal heme pocket with a relatively low electrostatic potential. Additionally, MtbFHb carries a new FAD binding site in its reductase domain similar to that of D-lactate dehydrogenase (D-LDH). When overexpressed in Escherichia coli or Mycobacterium smegmatis, MtbFHb remained associated with the cell membrane and exhibited D-lactate: phenazine methosulfate reductase activity and oxidized D-lactate into pyruvate by converting the heme iron from Fe3+ to Fe2+ in a FAD-dependent manner, indicating electron transfer from D-lactate to the heme via FAD cofactor. Under oxidative stress, MtbFHb-expressing cells exhibited growth advantage with reduced levels of lipid peroxidation. Given the fact that D-lactate is a byproduct of lipid peroxidation and that M. tuberculosis lacks the gene encoding D-LDH, we propose that the novel D-lactate metabolizing activity of MtbFHb uniquely equips M. tuberculosis to balance the stress level by protecting the cell membrane from oxidative damage via cycling between the Fe3+/Fe2+ redox states.
引用
收藏
页码:16435 / 16446
页数:12
相关论文
共 50 条
  • [1] GENITOURINARY TUBERCULOSIS: IS IT CLINICALLY RELEVANT TO DIFFERENTIATE MYCOBACTERIUM TUBERCULOSIS FROM MYCOBACTERIUM BOVIS?
    Quiroz Compean, Alejandro
    Cendejas Gomez, Jose de J.
    Garza Gangemi, Adrian M.
    Ponce de Leon, Alfredo
    Sotomayor de Zavaleta, Mariano J.
    Castillejos Molina, Ricardo A.
    JOURNAL OF UROLOGY, 2020, 203 : E1165 - E1165
  • [2] Nudix hydrolases from Mycobacterium tuberculosis
    Cunningham, J
    Foster, B
    Slivka, E
    O'Handley, S
    FASEB JOURNAL, 2001, 15 (04): : A173 - A173
  • [3] HAEMAGGLUTININS FROM MYCOBACTERIUM-TUBERCULOSIS
    BOYDEN, SV
    NATURE, 1950, 165 (4202) : 765 - 765
  • [4] Cobblestone Airway From Mycobacterium Tuberculosis
    Agustin, M.
    Yamamoto, M.
    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2024, 209
  • [5] Type I Flavohemoglobin of Mycobacterium Smegmatis Is a Functional Nitric Oxide Dioxygenase
    Thakur, Naveen
    Gupta, Sanjay
    Hade, Mangesh Dattu
    Dikshit, Kanak L.
    IUBMB LIFE, 2014, 66 (06) : 396 - 404
  • [6] Characterization of KmtR from Mycobacterium tuberculosis
    Higgins, Khadine
    Surette, Victoria
    Swanson, Gina
    Miller, Amanda
    Gonzalez, Katlyn
    McGowan, Mitchell
    Lewis, Stephanie
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2017, 254
  • [7] Transmission of Mycobacterium tuberculosis from an infant
    Reynolds, D. L.
    Gillis, F.
    Kitai, I.
    Deamond, S. L.
    Silverman, M.
    King, S. M.
    Matlow, A. G.
    Crockett, M.
    INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, 2006, 10 (09) : 1051 - 1056
  • [8] Nudix hydrolases from Mycobacterium tuberculosis
    Cunningham, J
    Foster, B
    Slivka, E
    O'Handley, SF
    BIOPHYSICAL JOURNAL, 2002, 82 (01) : 438A - 439A
  • [9] Reinfection with Mycobacterium tuberculosis -: From the authors
    Verver, S
    Warren, RM
    Beyers, N
    van der Spuy, GD
    van Helden, PD
    Borgdorff, MW
    Enarson, DA
    Behr, MA
    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2006, 173 (01) : 134 - 135
  • [10] Lessons from the Mycobacterium tuberculosis genome
    Garnier, T
    Brosch, R
    Eiglmeier, K
    Gordon, SV
    Cole, ST
    TUBERCULOSIS IN HUMAN AND VETERINARY MEDICINE, 1999, : 47 - 49