Three Sites and You Are Out: Ternary Synergistic Allostery Controls Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

Blackmore, Nicola J.; Reichau, Sebastian; Jiao, Wanting; Hutton, Richard D.; Baker, Edward N.; Jameson, Geoffrey B.; Parker, Emily J.

doi:10.1016/j.jmb.2012.12.019

Cited by 38 publications

(75 citation statements)

References 40 publications

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“…Key Arg residues, Arg-171 and Arg-256, are responsible for forming interactions with Phe and Tyr, respectively. Substitution of these Arg residues by Ala impairs the allosteric response of MtuDAH7PS activity to Phe and Tyr without compromising catalytic activity (9). We now demonstrate that hetero-octameric complex formation between MtuDAH7PS and MtuCM not only provides an activity boost for MtuCM, but, very significantly, also allows this enzyme to share the allosteric machinery of its much larger complex partner.…”

mentioning

confidence: 72%

“…The DAH7PS enzymes display a remarkably wide variety of allosteric mechanisms delivered by variable allosteric machinery appended to the core catalytic barrel (8). Of these, MtuDAH7PS appears to show the most sophisticated and elaborate allostery (9).…”

Section: Discussionmentioning

confidence: 99%

“…and MtuDAH7PS variants were prepared and purified as described previously (9,11,17). An MtuCM synthetic gene (Geneart), optimized for Escherichia coli codon usage, was transferred into pDEST 15 using Gateway cloning technology (Invitrogen).…”

Section: Expression and Purification Of Mtucm And Mtudah7ps-mtudah7psmentioning

confidence: 99%

“…binding sites that disrupt Phe and Tyr binding, were examined for their ability to activate MtuCM (9). MtuCM was similarly activated by MtuDAH7PS…”

Section: Variant Mtudah7ps Proteins With Impaired Tyr and Phe Bindingmentioning

confidence: 99%

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Complex Formation between Two Biosynthetic Enzymes Modifies the Allosteric Regulatory Properties of Both

Blackmore

Nazmi

Hutton

et al. 2015

Journal of Biological Chemistry

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Background: Two enzymes from Mycobacterium tuberculosis involved in aromatic amino acid biosynthesis form a heterooctameric complex. Results: Complex formation boosts the catalytic activity of both enzymes and greatly extends the allosteric effector sensitivity. Conclusion: Enzyme interactions allow complex allosteric machinery of one of the complex partners to be shared. Significance: Sophisticated allosteric responses are delivered through protein-protein interactions, allowing enhanced metabolic control.

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mentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Expression and Purification Of Mtucm And Mtudah7ps-mtudah7psmentioning

confidence: 99%

“…binding sites that disrupt Phe and Tyr binding, were examined for their ability to activate MtuCM (9). MtuCM was similarly activated by MtuDAH7PS…”

Section: Variant Mtudah7ps Proteins With Impaired Tyr and Phe Bindingmentioning

confidence: 99%

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Complex Formation between Two Biosynthetic Enzymes Modifies the Allosteric Regulatory Properties of Both

Blackmore

Nazmi

Hutton

et al. 2015

Journal of Biological Chemistry

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“…Type II enzymes are the most complex, and the only fully characterized example is from Mycobacterium tuberculosis (10). M. tuberculosis DAH7PS has multiple extensions to the core barrel providing three allosteric binding sites that work synergistically (11). In addition, this protein can form a non-covalent complex with the M. tuberculosis CM allowing for complex allosteric control of both CM and DAH7PS activities (12).…”

mentioning

confidence: 99%

Interdomain Conformational Changes Provide Allosteric Regulation en Route to Chorismate

Nazmi

Lang

Bai

et al. 2016

Journal of Biological Chemistry

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Multifunctional proteins play a variety of roles in metabolism.Here, we examine the catalytic function of the combined 3-deoxy-D-arabino heptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM) from Geobacillus sp. DAH7PS operates at the start of the biosynthetic pathway for aromatic metabolites, whereas CM operates in a dedicated branch of the pathway for the biosynthesis of amino acids tyrosine and phenylalanine. In line with sequence predictions, the two catalytic functions are located in distinct domains, and these two activities can be separated and retain functionality. For the full-length protein, prephenate, the product of the CM reaction, acts as an allosteric inhibitor for the DAH7PS. The crystal structure of the full-length protein with prephenate bound and the accompanying small angle x-ray scattering data reveal the molecular mechanism of the allostery. Prephenate binding results in the tighter association between the dimeric CM domains and the tetrameric DAH7PS, occluding the active site and therefore disrupting DAH7PS function. Acquisition of a physical gating mechanism to control catalytic function through gene fusion appears to be a general mechanism for providing allostery for this enzyme.

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The diversity of allosteric controls at the gateway to aromatic amino acid biosynthesis

Light

Anderson

2013

Protein Science

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Present within bacteria, plants, and some lower eukaryotes 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase (DAHPS) catalyzes the first committed step in the synthesis of a number of metabolites, including the three aromatic amino acids phenylalanine, tyrosine, and tryptophan. Catalyzing the first reaction in an important biosynthetic pathway, DAHPS is situated at a critical regulatory checkpoint-at which pathway input can be efficiently modulated to respond to changes in the concentration of pathway outputs. Based on a phylogenetic classification scheme, DAHPSs have been divided into three major subtypes (Ia, Ib, and II). These subtypes are subjected to an unusually diverse pattern of allosteric regulation, which can be used to further subdivide the enzymes. Crystal structures of most of the regulatory subclasses have been determined. When viewed collectively, these structures illustrate how distinct mechanisms of allostery are applied to a common catalytic scaffold. Here, we review structural revelations regarding DAHPS regulation and make the case that the functional difference between the three major DAHPS subtypes relates to basic distinctions in quaternary structure and mechanism of allostery.

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Three Sites and You Are Out: Ternary Synergistic Allostery Controls Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

Cited by 38 publications

References 40 publications

Complex Formation between Two Biosynthetic Enzymes Modifies the Allosteric Regulatory Properties of Both

Complex Formation between Two Biosynthetic Enzymes Modifies the Allosteric Regulatory Properties of Both

Interdomain Conformational Changes Provide Allosteric Regulation en Route to Chorismate

The diversity of allosteric controls at the gateway to aromatic amino acid biosynthesis

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