Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0220723 (PCA)
 4,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protocatechuate 3,4-dioxygenase (3,4-PCD) utilizes a ferric ion to catalyze the aromatic ring cleavage of 3,4-dihydroxybenzoate (PCA) by incorporation of both atoms of dioxygen to yield beta-carboxy-cis, cis-muconate. The crystal structures of the anaerobic 3,4-PCD.PCA complex, aerobic complexes with two heterocyclic PCA analogs, 2-hydroxyisonicotinic acid N-oxide (INO) and 6-hydroxynicotinic acid N-oxide (NNO), and ternary complexes of 3,4-PCD.INO.CN and 3,4-PCD. NNO.CN have been determined at 2.1-2.2 A resolution and refined to R-factors between 0.165 and 0.184. PCA, INO, and NNO form very similar, asymmetrically chelated complexes with the active site Fe3+ that result in dissociation of the endogenous axial tyrosinate Fe3+ ligand, Tyr447 (147beta). After its release from the iron, Tyr447 is stabilized by hydrogen bonding to Tyr16 (16alpha) and Asp413 (113beta) and forms the top of a small cavity adjacent to the C3-C4 bond of PCA. The equatorial Fe3+ coordination site within this cavity is unoccupied in the anaerobic 3,4-PCD.PCA complex but coordinates a solvent molecule in the 3,4-PCD.INO and 3,4-PCD.NNO complexes and CN- in the 3,4-PCD.INO.CN and 3,4-PCD.NNO.CN complexes. This shows that an O2 analog can occupy the cavity and suggests that electrophilic O2 attack on PCA is initiated from this site. Both the dissociation of the endogenous Tyr447 and the expansion of the iron coordination sphere are novel features of the 3,4-PCD. substrate complex which appear to play essential roles in the activation of substrate for O2 attack. Together, the structures presented here and in the preceding paper [Orville, A. M., Elango, N. , Lipscomb, J. D., & Ohlendorf, D. H. (1997) Biochemistry 36, 10039-10051] provide atomic models for several steps in the reaction cycle of 3,4-PCD and related Fe3+-containing dioxygenases.
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PMID:Crystal structures of substrate and substrate analog complexes of protocatechuate 3,4-dioxygenase: endogenous Fe3+ ligand displacement in response to substrate binding. 925

The crystal structures of protocatechuate 3,4-dioxygenase from the soil bacteria Acinetobacterstrain ADP1 (Ac 3,4-PCD) have been determined in space group I23 at pH 8.5 and 5.75. In addition, the structures of Ac 3,4-PCD complexed with its substrate 3, 4-dihydroxybenzoic acid (PCA), the inhibitor 4-nitrocatechol (4-NC), or cyanide (CN(-)) have been solved using native phases. The overall tertiary and quaternary structures of Ac 3,4-PCD are similar to those of the same enzyme from Pseudomonas putida[Ohlendorf et al. (1994) J. Mol. Biol. 244, 586-608]. At pH 8.5, the catalytic non-heme Fe(3+) is coordinated by two axial ligands, Tyr447(OH) (147beta) and His460(N)(epsilon)(2) (160beta), and three equatorial ligands, Tyr408(OH) (108beta), His462(N)(epsilon)(2) (162beta), and a hydroxide ion (d(Fe-OH) = 1.91 A) in a distorted bipyramidal geometry. At pH 5.75, difference maps suggest a sulfate binds to the Fe(3+) in an equatorial position and the hydroxide is shifted [d(Fe-OH) = 2.3 A] yielding octahedral geometry for the active site Fe(3+). This change in ligation geometry is concomitant with a shift in the optical absorbance spectrum of the enzyme from lambda(max) = 450 nm to lambda(max) = 520 nm. Binding of substrate or 4-NC to the Fe(3+) is bidentate with the axial ligand Tyr447(OH) (147beta) dissociating. The structure of the 4-NC complex supports the view that resonance delocalization of the positive character of the nitrogen prevents substrate activation. The cyanide complex confirms previous work that protocatechuate 3,4-dioxygenases have three coordination sites available for binding by exogenous substrates. A significant conformational change extending away from the active site is seen in all structures when compared to the native enzyme at pH 8.5. This conformational change is discussed in its relevance to enhancing catalysis in protocatechuate 3,4-dioxygenases.
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PMID:Structure of Acinetobacter strain ADP1 protocatechuate 3, 4-dioxygenase at 2.2 A resolution: implications for the mechanism of an intradiol dioxygenase. 1089 Oct 75