Role of metals in the reaction catalyzed by protein farnesyltransferase.

Abstract:

:Protein farnesyltransferase catalyzes the posttranslational farnesylation of several proteins involved in signal transduction, including Ras, and is a target enzyme for antitumor therapies. Efficient product formation catalyzed by protein farnesyltransferase requires an enzyme-bound zinc cation and high concentrations of magnesium ions. In this work, we have measured the pH dependence of the chemical step of product formation, determined under single-turnover conditions, and have demonstrated that the prenylation rate constant is enhanced by two deprotonations. Substitution of the active site zinc by cadmium demonstrated that one of the ionizations reflects deprotonation of the metal-coordinated thiol of the peptide "CaaX" motif, pK(a1) = 6.0. These data provide additional evidence for the direct involvement of a metal-coordinated sulfur nucleophile in catalysis. The second ionization was assigned to a hydroxyl on the pyrophosphate moiety of farnesyl pyrophosphate, pK(a2) = 7.4. Deprotonation of this group is important for binding of magnesium. This second ionization is not observed for catalysis in the absence of magnesium or when the substrate is farnesyl monophosphate. These data indicate that the maximal rate constant for prenylation requires formation of a zinc-coordinated thiolate nucleophile and enhancement of the electrophilic character at C1 of the farnesyl chain by magnesium ion coordination of the pyrophosphate leaving group.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Saderholm MJ,Hightower KE,Fierke CA

doi

10.1021/bi0011781

subject

Has Abstract

pub_date

2000-10-10 00:00:00

pages

12398-405

issue

40

eissn

0006-2960

issn

1520-4995

pii

bi0011781

journal_volume

39

pub_type

杂志文章
  • Control of P-glycoprotein activity by membrane cholesterol amounts and their relation to multidrug resistance in human CEM leukemia cells.

    abstract::P-glycoprotein (P-gp) is the most well-known ATP-binding cassette (ABC) transporter involved in unidirectional substrate translocation across the membrane lipid bilayer, thereby causing the typical multidrug resistance (MDR) phenotype expressed in many cancers. We observed that in human CEM acute lymphoblastic leukemi...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi048669w

    authors: Gayet L,Dayan G,Barakat S,Labialle S,Michaud M,Cogne S,Mazane A,Coleman AW,Rigal D,Baggetto LG

    更新日期:2005-03-22 00:00:00

  • Nearest neighbor analysis of the SecYEG complex. 2. Identification of a SecY-SecE cytosolic interface.

    abstract::Although the importance of interactions involving both the cytosolic and transmembrane regions of SecY and SecE has been documented, no information has been available for the physical contact sites of these translocase subunits in their cytosolic domains. We now carried out site-specific cross-linking experiments to i...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi034333v

    authors: Satoh Y,Mori H,Ito K

    更新日期:2003-06-24 00:00:00

  • Reconsidering the mechanism of polyglutamine peptide aggregation.

    abstract::There are at least nine neurodegenerative diseases associated with proteins that contain an unusually expanded polyglutamine domain, the best known of which is Huntington's disease. In all of these diseases, the mutant protein aggregates into neuronal inclusions; it is generally, although not universally, believed tha...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi700806c

    authors: Lee CC,Walters RH,Murphy RM

    更新日期:2007-11-06 00:00:00

  • Identification of a new class of inhibitors of the voltage-gated potassium channel, Kv1.3, with immunosuppressant properties.

    abstract::The voltage-gated potassium channel, K(v)1.3, is a novel target for development of immunosuppressants. Using a functional (86)Rb(+) efflux assay, a new class of high-affinity K(v)1.3 inhibitors has been identified. The initial active in this series, 4-phenyl-4-[3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl]cyclohexanone (P...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi025722c

    authors: Schmalhofer WA,Bao J,McManus OB,Green B,Matyskiela M,Wunderler D,Bugianesi RM,Felix JP,Hanner M,Linde-Arias AR,Ponte CG,Velasco L,Koo G,Staruch MJ,Miao S,Parsons WH,Rupprecht K,Slaughter RS,Kaczorowski GJ,Garcia ML

    更新日期:2002-06-18 00:00:00

  • Mechanism of pigeon liver malic enzyme: kinetics, specificity, and half-site stoichiometry of the alkylation of a cysteinyl residue by the substrate-inhibitor bromopyruvate.

    abstract::Malic enzyme from pigeon liver is alkylated by the substrate analogue bromopyruvate, resulting in the concomitant loss of its oxidative decarboxylase and oxalacetate decarboxylase activities, but not its ability to reduce alpha-keto acids. The inactivation of oxidative decarboxylase activity follows saturation kinetic...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00621a024

    authors: Chang GG,Hsu RY

    更新日期:1977-01-25 00:00:00

  • Mechanistic characterization of the bifunctional aminoglycoside-modifying enzyme AAC(3)-Ib/AAC(6')-Ib' from Pseudomonas aeruginosa.

    abstract::A recently discovered bifunctional antibiotic-resistance enzyme named AAC(3)-Ib/AAC(6')-Ib', from Pseudomonas aeruginosa, catalyzes acetylation of aminoglycoside antibiotics. Since both domains are acetyltransferases, each was cloned and purified for mechanistic studies. The AAC(3)-Ib domain appears to be highly speci...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi700111z

    authors: Kim C,Villegas-Estrada A,Hesek D,Mobashery S

    更新日期:2007-05-01 00:00:00

  • Cooperative binding of R17 coat protein to RNA.

    abstract::The binding of the R17 coat protein to synthetic RNAs containing one or two coat protein binding sites was characterized by using nitrocellulose filter and gel-retention assays. RNAs with two available sites bound coat protein in a cooperative manner, resulting in a higher affinity and reduced sensitivity to pH, ionic...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00502a006

    authors: Witherell GW,Wu HN,Uhlenbeck OC

    更新日期:1990-12-18 00:00:00

  • The metastasis-associated extracellular matrix protein osteopontin forms transient structure in ligand interaction sites.

    abstract::Osteopontin (OPN) is an acidic hydrophilic glycophosphoprotein that was first identified as a major sialoprotein in bones. It functions as a cell attachment protein displaying a RGD cell adhesion sequence and as a cytokine that signals through integrin and CD44 cell adhesion molecules. OPN is also implicated in human ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi200291e

    authors: Platzer G,Schedlbauer A,Chemelli A,Ozdowy P,Coudevylle N,Auer R,Kontaxis G,Hartl M,Miles AJ,Wallace BA,Glatter O,Bister K,Konrat R

    更新日期:2011-07-12 00:00:00

  • Hydrogen bond interactions of the pheophytin electron acceptor and its radical anion in photosystem II as revealed by Fourier transform infrared difference spectroscopy.

    abstract::The primary electron acceptor pheophytin (Pheo(D1)) plays a crucial role in regulation of forward and backward electron transfer in photosystem II (PSII). It is known that some cyanobacteria control the Pheo(D1) potential in high-light acclimation by exchanging the D1 proteins from different copies of the psbA genes. ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9018829

    authors: Shibuya Y,Takahashi R,Okubo T,Suzuki H,Sugiura M,Noguchi T

    更新日期:2010-01-26 00:00:00

  • Sequential domain unfolding in phosphoglycerate kinase: fluorescence intensity and anisotropy stopped-flow kinetics of several tryptophan mutants.

    abstract::Stopped-flow total intensity and anisotropy experiments on single tryptophan containing mutants of yeast phosphoglycerate kinase (PGK) located in either the carboxy-terminal domain (W308 and W333), amino-terminal domain (W48 and W122), or "hinge" region (W194 and W399) were performed. The results obtained for single t...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00042a028

    authors: Beechem JM,Sherman MA,Mas MT

    更新日期:1995-10-24 00:00:00

  • Cross-linked dimers with nucleating activity in actin prepared from muscle acetone powder.

    abstract::A covalently linked actin dimer is identified in solutions of actin prepared from an acetone powder from skeletal muscle. This actin dimer acts as an actin nucleating factor (ANF), decreasing the half-time for spontaneous actin polymerization. ANF reacts with antibodies to both the N- and C-terminal portions of actin ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9914964

    authors: Selden LA,Kinosian HJ,Estes JE,Gershman LC

    更新日期:2000-01-11 00:00:00

  • Low concentrations of bile salts increase the rate of spontaneous phospholipid transfer between vesicles.

    abstract::The rate of 1-palmitoyl-2-[12-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino] dodecanoyl] phosphatidylcholine (P-C12-NBD-PC) transfer between dioleoylphosphatidylcholine vesicles was measured by a technique based on resonance energy transfer between P-C12-NBD-PC and N-(lissamine rhodamine B sulfonyl)dioleoylphosphatidyletha...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00364a021

    authors: Nichols JW

    更新日期:1986-08-12 00:00:00

  • Zn(2+)-dependent misfolding of the p53 DNA binding domain.

    abstract::The DNA binding domain (DBD) of p53 folds by a complex mechanism that involves parallel pathways and multiple intermediates, both on- and off-pathway. This heterogeneity renders DBD particularly susceptible to misfolding and aggregation. The origins of parallel folding mechanisms are not well understood. DBD folding h...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi062106y

    authors: Butler JS,Loh SN

    更新日期:2007-03-13 00:00:00

  • Preparation and characterization of N-(1-pyrenyl)iodoacetamide-labeled Escherichia coli RNA polymerase.

    abstract::N-(1-Pyrenyl)iodoacetamide has been used to introduce fluorescent probes into Escherichia coli RNA polymerase. After an incubation time of 15 min, approximately 2 pyrene equiv was introduced per enzyme molecule. There was no further increase in modification after more extended periods of incubation. Neither calf thymu...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00215a028

    authors: Johnson RS,Bowers M,Eaton Q

    更新日期:1991-01-08 00:00:00

  • Perturbation of microtubule polymerization by quercetin through tubulin binding: a novel mechanism of its antiproliferative activity.

    abstract::The dietary flavonoid quercetin has a broad range of biological activities, including potent antitumor activity against several types of tumors. Recently, it has been shown that quercetin inhibits cancer cells proliferation by depleting cellular microtubules and perturbing cellular microtubule functions. However, the ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi025952r

    authors: Gupta K,Panda D

    更新日期:2002-10-29 00:00:00

  • Electrophoretic analysis of substrate-attached proteins from normal and virus-transformed cells.

    abstract::The proteins which have been left tightly bound to the tissue culture substrate after ethylenebis (oxyethyl-enenitrilo) tetraacetic acid (EGTA)-mediated removal of normal, virus-transformed, and revertant mouse cells and which have been implicated in the substrate adhesion process have been analyzed by slab sodium dod...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00663a028

    authors: Culp LA

    更新日期:1976-09-07 00:00:00

  • Codon-induced association of the isolated anticodon loop of tRNAPhe.

    abstract::The binding of the codon UUC to the isolated anticodon loop of tRNAPhe (yeast) has been studied as a model of codon recognition by a simple adaptor. Fluorescence titrations demonstrate that UUC binds to the isolated anticodon loop with an equilibrium constant of 1.4 X 10(3) M-1 (at 7.2 degrees C). Equilibrium sediment...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00369a005

    authors: Bujalowski W,Jung M,McLaughlin LW,Porschke D

    更新日期:1986-10-21 00:00:00

  • Topography of the Dictyostelium discoideum plasma membrane: analysis of membrane asymmetry and intermolecular disulfide bonds.

    abstract::Through the application of a unique method for isolating plasma membranes, it was possible to specifically iodinate cytoplasm-exposed plasma membrane proteins in vegetative cells of the cellular slime mold Dictyostelium discoideum. The original procedure [Chaney, L. K., & Jacobson, B. S. (1983) J. Biol. Chem. 258, 100...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00389a041

    authors: Shiozawa JA,Jelenska MM,Jacobson BS

    更新日期:1987-07-28 00:00:00

  • Nitroxides block DNA scission and protect cells from oxidative damage.

    abstract::The protective effect of cyclic stable nitroxide free radicals, having SOD-like activity, against oxidative damage was studied by using Escherichia coli xthA DNA repair-deficient mutant hypersensitive to H2O2. Oxidative damage induced by H2O2 was assayed by monitoring cell survival. The metal chelator 1,10-phenanthrol...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00216a033

    authors: Samuni A,Godinger D,Aronovitch J,Russo A,Mitchell JB

    更新日期:1991-01-15 00:00:00

  • Inhibition of sodium-calcium exchange in cardiac sarcolemmal membrane vesicles. 1. Mechanism of inhibition by amiloride analogues.

    abstract::The mechanism by which terminal guanidino nitrogen substituted analogues of amiloride inhibit Na-Ca exchange in purified cardiac sarcolemmal membrane vesicles has been investigated. These inhibitors block both Nai-dependent Ca2+ uptake and Nao-dependent Ca2+ efflux. Inhibition of Na-Ca exchange monitored in K+ is nonc...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00407a023

    authors: Slaughter RS,Garcia ML,Cragoe EJ Jr,Reeves JP,Kaczorowski GJ

    更新日期:1988-04-05 00:00:00

  • A hydrophobic inhibitor of the nicotinic acetylcholine receptor acts on the resting state.

    abstract::3-(Trifluoromethyl)-3-(m-iodophenyl)diazirine (TID) has recently been found to be a noncompetitive inhibitor of the nicotinic acetylcholine receptor (nAcChoR) by both photolabeling and flux assays (White et al., 1991). However, these experiments were done when TID was in equilibrium with the nAcChoR, and thus only its...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00255a018

    authors: Wu G,Raines DE,Miller KW

    更新日期:1994-12-27 00:00:00

  • Structural characterization of the interaction of the delta and alpha subunits of the Escherichia coli F1F0-ATP synthase by NMR spectroscopy.

    abstract::A critical point of interaction between F(1) and F(0) in the bacterial F(1)F(0)-ATP synthase is formed by the alpha and delta subunits. Previous work has shown that the N-terminal domain (residues 3-105) of the delta subunit forms a 6 alpha-helix bundle [Wilkens, S., Dunn, S. D., Chandler, J., Dahlquist, F. W., and Ca...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi0510678

    authors: Wilkens S,Borchardt D,Weber J,Senior AE

    更新日期:2005-09-06 00:00:00

  • Crystal structures of potent thiol-based inhibitors bound to carboxypeptidase B.

    abstract::This paper presents the crystal structure of porcine pancreatic carboxypeptidase B (pp-CpB) in complex with a variety of thiol-based inhibitors that were developed as antagonists of activated thrombin-activatable fibrinolysis inhibitor (TAFIa). Recent studies have indicated that a selective inhibitor of TAFIa could en...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi0501941

    authors: Adler M,Bryant J,Buckman B,Islam I,Larsen B,Finster S,Kent L,May K,Mohan R,Yuan S,Whitlow M

    更新日期:2005-07-05 00:00:00

  • Splicing Site Recognition by Synergy of Three Domains in Splicing Factor RBM10.

    abstract::Splicing factor RBM10 and its close homologues RBM5 and RBM6 govern the splicing of oncogenes such as Fas, NUMB, and Bcl-X. The molecular architecture of these proteins includes zinc fingers (ZnFs) and RNA recognition motifs (RRMs). Three of these domains in RBM10 that constitute the RNA binding part of this splicing ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.7b01242

    authors: Serrano P,Hammond JA,Geralt M,Wüthrich K

    更新日期:2018-03-13 00:00:00

  • Pre-steady-state kinetics reveal a slow isomerization of the enzyme-NAD complex in the NAD-malic enzyme reaction.

    abstract::Stopped-flow experiments obtained in the pre-steady-state time scale of the NAD-malic enzyme reaction exhibit a lag prior to the attainment of steady state. Previous results from isotope effect studies in which the deuterium isotope effect on Vmax decreases to a value of 1 at low pH have been interpreted as suggesting...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00059a007

    authors: Rajapaksa R,Abu-Soud H,Raushel FM,Harris BG,Cook PF

    更新日期:1993-03-02 00:00:00

  • G-protein-dependent cell surface dynamics of the human serotonin1A receptor tagged to yellow fluorescent protein.

    abstract::Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive, behavioral, and developmental processes. The serotonin(1A) receptor is an important member of the superfamily of seven transmembrane domain G-protein-coupled receptors and is the most extensively studied among the ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi0480887

    authors: Pucadyil TJ,Kalipatnapu S,Harikumar KG,Rangaraj N,Karnik SS,Chattopadhyay A

    更新日期:2004-12-21 00:00:00

  • Characterization and purification of the discoidin domain-containing protein retinoschisin and its interaction with galactose.

    abstract::RS1, also known as retinoschisin, is an extracellular discoidin domain-containing protein that has been implicated in maintaining the cellular organization and synaptic structure of the vertebrate retina. Mutations in the gene encoding RS1 are responsible for X-linked retinoschisis, a retinal degenerative disease char...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi800938g

    authors: Dyka FM,Wu WW,Pfeifer TA,Molday LL,Grigliatti TA,Molday RS

    更新日期:2008-09-02 00:00:00

  • N-linked neutral sugar chains of aminopeptidase N purified from rat small intestinal brush-border membrane.

    abstract::Neutral oligosaccharides, which accounted for 74% of the total N-linked sugar chains released by hydrazinolysis of rat small intestinal aminopeptidase N, were investigated on a structural basis. They are mainly composed of complex-type sugar chains with tri- and tetraantennary structures, and small amounts of high man...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00101a028

    authors: Takasaki S,Erickson RH,Kim YS,Kochibe N,Kobata A

    更新日期:1991-09-17 00:00:00

  • A Biochemical Lanthanide-Encoding Approach Enables Quantitative Monitoring of the Bacterial Response to Vancomycin Treatment.

    abstract::A pathogenic bacterium has its own mechanisms for not only pathogenic attack but also exogenous invasion defense, in which the bacterial cell wall is the front line of attack and defense. We developed a biochemical lanthanide-encoding approach to quantify the uncanonical d-amino acid (d-X) that was edited in a small p...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.0c00614

    authors: Zhao W,Liang Y,Yan X,Yang L,Wang Q

    更新日期:2020-09-29 00:00:00

  • Substrate recognition determinants for rhodopsin kinase: studies with synthetic peptides, polyanions, and polycations.

    abstract::Rhodopsin kinase phosphorylates serine- and threonine-containing peptides from bovine rhodopsin's carboxyl-terminal sequence. Km's for the peptides decrease as the length of the peptide is increased over the range 12-31 amino acids, reaching 1.7 mM for peptide 318-348 from the rhodopsin sequence. The Km for phosphoryl...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00448a013

    authors: Palczewski K,Arendt A,McDowell JH,Hargrave PA

    更新日期:1989-10-31 00:00:00