Hydroxamates and aliphatic boronic acids: marker inhibitors for aminopeptidase

Baker, John O.; Wilkes, Stella H.; Bayliss, Mary E.; Prescott, J. M.

doi:10.1021/bi00278a009

Cited by 67 publications

(55 citation statements)

References 28 publications

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“…AAP activity was measured by the method of Prescott and Wilkes [18] as modified by Baker et al [20]. In this assay, the hydrolysis of 0.5 mM L-leucine p-nitroanilide (L-pNA) (10 mM Tricine, pH 8.0) was measured spectrophotometrically at 25°C by monitoring the formation of p-nitroaniline.…”

Section: Spectrophotometric Assaymentioning

confidence: 99%

X-ray crystallographic characterization of the Co(II)-substituted Tris-bound form of the aminopeptidase from Aeromonas proteolytica

Munih

Moulin

Stamper

et al. 2007

Journal of Inorganic Biochemistry

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The X-ray crystal structure of the Co(II)-loaded form of the aminopeptidase from Aeromonas proteolytica ([CoCo(AAP)]) was solved to 2.2A resolution. [CoCo(AAP)] folds into an alpha/beta globular domain with a twisted beta-sheet hydrophobic core sandwiched between alpha-helices, identical to [ZnZn(AAP)]. Co(II) binding to AAP does not introduce any major conformational changes to the overall protein structure and the amino acid residues ligated to the dicobalt(II) cluster in [CoCo(AAP)] are the same as those in the native Zn(II)-loaded structure with only minor perturbations in bond lengths. The Co(II)-Co(II) distance is 3.3A. Tris(hydroxymethyl)aminomethane (Tris) coordinates to the dinuclear Co(II) active site of AAP with one of the Tris hydroxyl oxygen atoms (O4) forming a single oxygen atom bridge between the two Co(II) ions. This is the only Tris atom coordinated to the metals with Co1-O and Co2-O bonds distances of 2.2 and 1.9A, respectively. Each of the Co(II) ions resides in a distorted trigonal bipyramidal geometry. This important structure bridges the gap between previous structural and spectroscopic studies performed on AAP and is discussed in this context.

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Section: Spectrophotometric Assaymentioning

confidence: 99%

X-ray crystallographic characterization of the Co(II)-substituted Tris-bound form of the aminopeptidase from Aeromonas proteolytica

Munih

Moulin

Stamper

et al. 2007

Journal of Inorganic Biochemistry

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“…the iron-containing enzyme ribonucleotide reductase (Kjoller Larsen, Sj6berg & Thelander, 1982), the nickel-containing enzyme urease (Dixon, Hinds, Fihelly, Gazzola, Winzor, Blakeley & Zerner, 1980), and zinc-or manganese-containing aminopeptidases Baker, Wilkes, Bayliss & Prescott, 1983). The inhibitory effect 0108-7681/88/050527-07503.00 of hydroxamic acids on ribonucleotide reductase has been shown to be due to the ability of the compounds to react with (reduce) the tyrosine free-radical group present in the subunit B2 of this enzyme (Kjoller Larsen et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Structural characteristics of the hydroxamic acid group. Crystal structure of formohydroxamic acid

Larsen¹

1988

Acta Crystallogr Sect B

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“…A possible explanation for the synergistic effect observed may be linked to the known property of hydroxamates to form a bidented ligand with zinc in metalloproteins (37,38). We hypothesize that ddI, acting on the complex involved in retrotranscription as a reverse transcriptase inhibitor, may facilitate the interaction of hydroxamates with certain HIV proteins such as ribonuclease H, where several metal ion binding sites have recently been described (39), and/or with the P7NC nucleocapside protein, which contains two retroviral zinc-finger sequences (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Synergistic anti-human immunodeficiency virus type 1 effect of hydroxamate compounds with 2',3'-dideoxyinosine in infected resting human lymphocytes.

Malley¹,

Grange²,

Hamedi-Sangsari³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The cellular models generally used in the in vitro evaluation of anti-human immunodeficiency virus compounds are dividing cells. A model constituted by resting lymphocytes may more accurately reflect a drug's future efficacy in humans, since viral DNA synthesis is known to take place in quiescent cells, creating a reservoir of infected cells awaiting activation to complete their viral replication cycle and to produce infectious virions. We report here the activity of 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, and two hydroxamates, D-aspartic acid jhydroxamate and hydroxycarbamide (hydroxyurea), alone and in various comnbinations, in an in vitro model based on resting lymphocytes. In our model, resting peripheral blood lymphocytes were infected with human immunodeficiency virus type 1 and treated with drugs for 7 days, at which time drugs were removed and the cells were activated by phytohemagglutinin.We show that under these conditions 3-azido-3'-deoxythymidine, 2',3'-dideoxyinosine, and 2',3'-dideoxycytidine, alone or in combination, neither fully inhibit viral production nor protect lymphocytes from the cytopathic effect of viral replication, at concentrations corresponding to the peak plasma levels observed in a typical treatment schedule in humans. In contrast, we report the synergistic effect of treatment by each hydroxamate with 2',3'-dideoxyinosine of infected resting lymphocytes, resulting in the total suppression of viral production, total protection against the cytopathic effect induced by viral replication, and no effect on the ability of the cells to replicate in this cell culture system.

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Hydroxamates and aliphatic boronic acids: marker inhibitors for aminopeptidase

Cited by 67 publications

References 28 publications

X-ray crystallographic characterization of the Co(II)-substituted Tris-bound form of the aminopeptidase from Aeromonas proteolytica

X-ray crystallographic characterization of the Co(II)-substituted Tris-bound form of the aminopeptidase from Aeromonas proteolytica

Structural characteristics of the hydroxamic acid group. Crystal structure of formohydroxamic acid

Synergistic anti-human immunodeficiency virus type 1 effect of hydroxamate compounds with 2',3'-dideoxyinosine in infected resting human lymphocytes.

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