Allosteric inhibition of Staphylococcus aureus MenD by 1,4-dihydroxy naphthoic acid: a feedback inhibition mechanism of the menaquinone biosynthesis pathway

Author:

Stanborough Tamsyn1,Ho Ngoc Anh Thu12,Bulloch Esther M. M.32,Bashiri Ghader32,Dawes Stephanie S.32,Akazong Etheline W.12,Titterington James1,Allison Timothy M.12,Jiao Wanting42ORCID,Johnston Jodie M.12ORCID

Affiliation:

1. School of Physical and Chemical Sciences, Biomolecular Interaction Centre (BIC), University of Canterbury, Christchurch 8041, New Zealand

2. Maurice Wilkins Centre for Molecular Biodiscovery, c/o The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

3. School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand

4. Ferrier Research Institute, Victoria University of Wellington, PO Box 600, Wellington 6140, New Zealand

Abstract

Menaquinones (MKs) are electron carriers in bacterial respiratory chains. In Staphylococcus aureus ( Sau ), MKs are essential for aerobic and anaerobic respiration. As MKs are redox-active, their biosynthesis likely requires tight regulation to prevent disruption of cellular redox balance. We recently found that the Mycobacterium tuberculosis MenD, the first committed enzyme of the MK biosynthesis pathway, is allosterically inhibited by the downstream metabolite 1,4-dihydroxy-2-naphthoic acid (DHNA). To understand if this is a conserved mechanism in phylogenetically distant genera that also use MK, we investigated whether the Sau- MenD is allosterically inhibited by DHNA. Our results show that DHNA binds to and inhibits the SEPHCHC synthase activity of Sau -MenD enzymes. We identified residues in the DHNA binding pocket that are important for catalysis (Arg98, Lys283, Lys309) and inhibition (Arg98, Lys283). Furthermore, we showed that exogenous DHNA inhibits the growth of Sau , an effect that can be rescued by supplementing the growth medium with MK-4. Our results demonstrate that, despite a lack of strict conservation of the DHNA binding pocket between Mtb -MenD and Sau -MenD, feedback inhibition by DHNA is a conserved mechanism in Sau -MenD and hence the Sau MK biosynthesis pathway. These findings may have implications for the development of anti-staphylococcal agents targeting MK biosynthesis. This article is part of the theme issue ‘Reactivity and mechanism in chemical and synthetic biology’.

Funder

Canterbury Medical Research Foundation

Royal Society Te Apārangi

Maurice Wilkins Centre for Molecular Biodiscovery

Health Research Council of New Zealand

Biomolecular Interaction Centre

Publisher

The Royal Society

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

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