2010
DOI: 10.1074/jbc.m110.107177
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Structural Basis for the Activity and Substrate Specificity of Fluoroacetyl-CoA Thioesterase FlK

Abstract: The thioesterase FlK from the fluoroacetate-producing Streptomyces cattleya catalyzes the hydrolysis of fluoroacetyl-coenzyme A. This provides an effective self-defense mechanism, preventing any fluoroacetyl-coenzyme A formed from being further metabolized to 4-hydroxy-trans-aconitate, a lethal inhibitor of the tricarboxylic acid cycle. Remarkably, FlK does not accept acetyl-coenzyme A as a substrate. Crystal structure analysis shows that FlK forms a dimer, in which each subunit adopts a hot dog fold as observ… Show more

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Cited by 24 publications
(46 citation statements)
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“…Sequence homologues of the Arthrobacter 4-HB-CoA thioesterase which have known physiological substrates include the bacterial phenylacetyl-CoA thioesterase (34), benzoyl-CoA thioesterase (35), enterobactin biosynthetic pathway “housekeeper” thioesterase EntH (8, 36, 37), long chain acyl-CoA thioesterase II and III (37, 38) and fluoroacetyl-CoA thioesterase (39-41). Sequence alignments of these homologues show conservation of Thr77 yet substitutions of Glu73 with an Asp residue and Gln58 with either an Asn or Glu residue.…”
Section: Resultsmentioning
confidence: 99%
“…Sequence homologues of the Arthrobacter 4-HB-CoA thioesterase which have known physiological substrates include the bacterial phenylacetyl-CoA thioesterase (34), benzoyl-CoA thioesterase (35), enterobactin biosynthetic pathway “housekeeper” thioesterase EntH (8, 36, 37), long chain acyl-CoA thioesterase II and III (37, 38) and fluoroacetyl-CoA thioesterase (39-41). Sequence alignments of these homologues show conservation of Thr77 yet substitutions of Glu73 with an Asp residue and Gln58 with either an Asn or Glu residue.…”
Section: Resultsmentioning
confidence: 99%
“…These two hotdog domains associate together with the two central -helices aligning together and the two -sheets associating through strands 3 and 9 to form an extended -sheet. In other thioesterase families (TE2, TE6 and TE7), these hotdog folds self-associate into higher order configurations depending on the thioesterase class, ranging from dimers (Dias et al, 2010) and tetramers (back to back or face to face; Tilton et al, 2004) to hexamers (trimer of dimers configuration; Forwood et al, 2007;Pidugu et al, 2009). Based on the structure of the E. coli TesB structure, the TesB enzymes are believed to function as a double-hotdog protomer (Li et al, 2000;Pidugu et al, 2009).…”
Section: Introductionmentioning
confidence: 99%
“…Consequently, there exists a natural selective pressure on S. cattleya to meet this challenge, and it has evolved a fluoroacetyl-CoA thioesterase (FlK) that catalyzes the breakdown of fluoroacetyl-CoA to prevent lethal synthesis of fluorocitrate (Fig. 1A) (22)(23)(24). We have recently shown that FlK demonstrates an extremely high, 10 6 -fold selectivity for hydrolysis of fluoroacetyl-CoA over acetyl-CoA based on a decrease in K m (10 2 ) and increase in k cat (10 4 ) for the fluorinated substrate (24).…”
mentioning
confidence: 99%