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The structure of alanine racemase from Acinetobacter baumannii.

Davis E, Scaletti-Hutchinson E, Opel-Reading H, Nakatani Y, Krause KL - Acta Crystallogr F Struct Biol Commun (2014)

Bottom Line: As D-alanine is an essential component of the bacterial cell wall, its inhibition is lethal to prokaryotes, making it an excellent antibiotic drug target.The substrate entryway and active site of the enzymes were shown to be highly conserved.The structure of AlrAba will provide the template required for future structure-based drug-design studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.

ABSTRACT
Acinetobacter baumannii is an opportunistic Gram-negative bacterium which is a common cause of hospital-acquired infections. Numerous antibiotic-resistant strains exist, emphasizing the need for the development of new antimicrobials. Alanine racemase (Alr) is a pyridoxal 5'-phosphate dependent enzyme that is responsible for racemization between enantiomers of alanine. As D-alanine is an essential component of the bacterial cell wall, its inhibition is lethal to prokaryotes, making it an excellent antibiotic drug target. The crystal structure of A. baumannii alanine racemase (AlrAba) from the highly antibiotic-resistant NCTC13302 strain has been solved to 1.9 Å resolution. Comparison of AlrAba with alanine racemases from closely related bacteria demonstrates a conserved overall fold. The substrate entryway and active site of the enzymes were shown to be highly conserved. The structure of AlrAba will provide the template required for future structure-based drug-design studies.

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Cα-atom superposition of AlrAba and other alanine racemases. Colouring is as follows: A. baumannii, green; P. aeruginosa, red; B. henselae, blue; E. coli, orange. Cα-­atom traces showing superposition between the (a) N-terminal and (b) C-terminal domains. (c) Superposition of the N-terminal α/β-barrel domain of whole alanine racemase monomers visualized as a ribbon representation. The PLP cofactor of AlrAba is depicted as a black ball-and-stick model. The difference in inter-monomer hinge angle between the enzymes is indicated by a black double-headed arrow. This figure was produced in PyMOL (DeLano, 2002 ▶).
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fig4: Cα-atom superposition of AlrAba and other alanine racemases. Colouring is as follows: A. baumannii, green; P. aeruginosa, red; B. henselae, blue; E. coli, orange. Cα-­atom traces showing superposition between the (a) N-terminal and (b) C-terminal domains. (c) Superposition of the N-terminal α/β-barrel domain of whole alanine racemase monomers visualized as a ribbon representation. The PLP cofactor of AlrAba is depicted as a black ball-and-stick model. The difference in inter-monomer hinge angle between the enzymes is indicated by a black double-headed arrow. This figure was produced in PyMOL (DeLano, 2002 ▶).

Mentions: The N-terminal domain of AlrAba superimposed best with those from AlrEco and DadXPao, with which it shares the highest sequence identity (40 and 39%, respectively) and the lowest r.m.s differences (1.32 and 1.30 Å, respectively). Consistent with the superpositions involving whole monomers, the N-terminal domain was less similar to that of AlrBhe (Fig. 4 ▶a). In the C-terminal domain, AlrAba superimposed equally well with AlrBhe, AlrEco and DadXPao (1.07, 1.02 and 1.08 Å, respectively; Fig. 4 ▶b). Analysis of the active sites indicates that this region superimposed the best, having much lower r.m.s differences than whole monomers or individual domains (AlrBhe, 0.91 Å; AlrEco, 0.65 Å; DadXPao, 0.56 Å). This indicates that the active site is highly conserved between the alanine racemase structures in spite of structural deviations between their domains.


The structure of alanine racemase from Acinetobacter baumannii.

Davis E, Scaletti-Hutchinson E, Opel-Reading H, Nakatani Y, Krause KL - Acta Crystallogr F Struct Biol Commun (2014)

Cα-atom superposition of AlrAba and other alanine racemases. Colouring is as follows: A. baumannii, green; P. aeruginosa, red; B. henselae, blue; E. coli, orange. Cα-­atom traces showing superposition between the (a) N-terminal and (b) C-terminal domains. (c) Superposition of the N-terminal α/β-barrel domain of whole alanine racemase monomers visualized as a ribbon representation. The PLP cofactor of AlrAba is depicted as a black ball-and-stick model. The difference in inter-monomer hinge angle between the enzymes is indicated by a black double-headed arrow. This figure was produced in PyMOL (DeLano, 2002 ▶).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4157418&req=5

fig4: Cα-atom superposition of AlrAba and other alanine racemases. Colouring is as follows: A. baumannii, green; P. aeruginosa, red; B. henselae, blue; E. coli, orange. Cα-­atom traces showing superposition between the (a) N-terminal and (b) C-terminal domains. (c) Superposition of the N-terminal α/β-barrel domain of whole alanine racemase monomers visualized as a ribbon representation. The PLP cofactor of AlrAba is depicted as a black ball-and-stick model. The difference in inter-monomer hinge angle between the enzymes is indicated by a black double-headed arrow. This figure was produced in PyMOL (DeLano, 2002 ▶).
Mentions: The N-terminal domain of AlrAba superimposed best with those from AlrEco and DadXPao, with which it shares the highest sequence identity (40 and 39%, respectively) and the lowest r.m.s differences (1.32 and 1.30 Å, respectively). Consistent with the superpositions involving whole monomers, the N-terminal domain was less similar to that of AlrBhe (Fig. 4 ▶a). In the C-terminal domain, AlrAba superimposed equally well with AlrBhe, AlrEco and DadXPao (1.07, 1.02 and 1.08 Å, respectively; Fig. 4 ▶b). Analysis of the active sites indicates that this region superimposed the best, having much lower r.m.s differences than whole monomers or individual domains (AlrBhe, 0.91 Å; AlrEco, 0.65 Å; DadXPao, 0.56 Å). This indicates that the active site is highly conserved between the alanine racemase structures in spite of structural deviations between their domains.

Bottom Line: As D-alanine is an essential component of the bacterial cell wall, its inhibition is lethal to prokaryotes, making it an excellent antibiotic drug target.The substrate entryway and active site of the enzymes were shown to be highly conserved.The structure of AlrAba will provide the template required for future structure-based drug-design studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.

ABSTRACT
Acinetobacter baumannii is an opportunistic Gram-negative bacterium which is a common cause of hospital-acquired infections. Numerous antibiotic-resistant strains exist, emphasizing the need for the development of new antimicrobials. Alanine racemase (Alr) is a pyridoxal 5'-phosphate dependent enzyme that is responsible for racemization between enantiomers of alanine. As D-alanine is an essential component of the bacterial cell wall, its inhibition is lethal to prokaryotes, making it an excellent antibiotic drug target. The crystal structure of A. baumannii alanine racemase (AlrAba) from the highly antibiotic-resistant NCTC13302 strain has been solved to 1.9 Å resolution. Comparison of AlrAba with alanine racemases from closely related bacteria demonstrates a conserved overall fold. The substrate entryway and active site of the enzymes were shown to be highly conserved. The structure of AlrAba will provide the template required for future structure-based drug-design studies.

Show MeSH
Related in: MedlinePlus