Catalytic Mechanisms of Metallohydrolases Containing Two Metal Ions

Mitić, Nataša; Miraula, Manfredi; Selleck, Christopher; Hadler, Kieran S.; Uribe, Elena; Pedroso, Marcelo Monteiro; Schenk, Gerhard

doi:10.1016/bs.apcsb.2014.07.002

Cited by 66 publications

(96 citation statements)

References 155 publications

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“…B2 subgroup) and binuclear (i.e. B1, B3 and B4 subgroups) MBLs have been published, with a common theme involving a nucleophilic hydroxide group that is either terminally bound (B2 MBLs) or bridging both metals (B1, B3 and B4 MBLs) (15,19,65,105,124,139,(148)(149)(150)(151)(152)(153) . Figure 1.10 illustrates simplified mechanistic schemes for both models using a truncated penicillin molecule as the substrate.…”

Section: Metallo β Lactamasesmentioning

confidence: 99%

“…OPdegrading BMHs) (12) . Furthermore, some BMHs such as MBLs appear to require Zn 2+ in vivo, however, in vitro activity can be reconstituted with a range of other divalent metal ions (15) . Such metal ion replacements are frequently exploited in functional studies where the catalytic and spectroscopic properties of different metal ion derivatives of an enzyme are compared to probe its mechanism of action.…”

Section: Selection and Function Of Metals In Bmhsmentioning

confidence: 99%

“…β-Lactamases are divided into four groups based on their mechanism of hydrolysis and cofactor requirements (66) . Groups A, C and D are serine-β-lactamases (SBLs), which employ a serine residue to initiate the hydrolysis of the β-lactam ring (i.e.…”

Section: β-Lactamases and Their Functionmentioning

confidence: 99%

“…These include the serine-β-lactamases (SBLs), which employ a serine residue to initiate the hydrolysis of the β-lactam ring (i.e. its opening), and metallo-β-lactamases (MBLs), which require either one or two metal ions in their active site as essential cofactors for catalysis (15,16,150,156,208) . MBLs are further sub-divided into as many as four sub-groups, i.e.…”

Section: 1introductionmentioning

confidence: 99%

“…These compounds are very effective in impeding the enzymes involved in the generation of peptidoglycans in the cell wall of pathogenic bacteria (16,150,156,208) . β-Lactamases are divided into two main classes based on their mechanism of action and cofactor requirements (15,16,150,156,208) . These include the serine-β-lactamases (SBLs), which employ a serine residue to initiate the hydrolysis of the β-lactam ring (i.e.…”

Section: 1introductionmentioning

confidence: 99%

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Kinetic, mechanistic, structural and spectroscopic investigations of Bimetallic Metallohydrolases

Selleck¹

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Section: Metallo β Lactamasesmentioning

confidence: 99%

Section: Selection and Function Of Metals In Bmhsmentioning

confidence: 99%

Section: β-Lactamases and Their Functionmentioning

confidence: 99%

Section: 1introductionmentioning

confidence: 99%

Section: 1introductionmentioning

confidence: 99%

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Kinetic, mechanistic, structural and spectroscopic investigations of Bimetallic Metallohydrolases

Selleck¹

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Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

Cheng,

Shi,

et al. 2023

Advanced Science

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Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen‐sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the “lactate shuttle”. Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species‐related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.

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The Binding Mode of an ADP Analogue to a Metallohydrolase Mimics the Likely Transition State

et al. 2019

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Purple acid phosphatases( PAPs) are members of the large family of metallohydrolases, ag roup of enzymes that perform aw ide range of biological functions, while employing ah ighly conserved catalytic mechanism. PAPs are found in plants,a nimals and fungi;i nh umans they play an important role in bone turnovera nd are thus of interest for developingt reatments for osteoporosis. The majority of metallohydrolases use am etalbound hydroxide to initiate catalysis, which leads to the formation of ap roposed five-coordinate oxyphosphorane species in the transition state. In this work, we crystallized PAPf rom red kidney beans (rkbPAP) in the presence of both adenosine and vanadate. The in crystallo-formed vanadate analogue of ADP provides detailed insight into the binding mode of aP AP substrate, captured in as tructure that mimics the putative fivecoordinate transition state. Our observations not only provide unprecedented insightinto the mechanism of metallohydrolases, but might also guide the structure-based design of inhibitors for application in the treatment of severalhuman illnesses.Metallohydrolases form al arge familyo fm ostly bimetallic enzymes that use metal ionst oactivate both the nucleophile and scissile bond of various phosphate or amide substrates. [1][2][3][4] Examples include the antibiotic-degrading metallo-b-lactamases, pesticide-decontaminating organophosphate hydrolases, and purple acid phosphatases (PAPs). [5][6][7] PAPs, the only known metallohydrolases that require ah eterovalent Fe III M II center (with M = Fe, Zn or Mn) for catalytic activity, have been characterized from various mammals, plants and fungi. [2,5] Mostp lant PAPs use either Zn II or Mn II ,w hereas their mammalianc ounterparts employ ar edox-activei ron ( Figure 1). [8,9] The reported substrates for PAPs include adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate( ADP), phosphotyrosine and pyrophosphate. [5,10] The synthetic substrate para-nitrophenyl phosphate (pNPP) is frequently used for functionalstudies. [2,5] The biological functions of PAPs are diverse and dependent on the organism. For mammals, experiments with transgenic mice have demonstrated that PAPp lays an important role in bone metabolism. [11,12] In plants, PAPs playamajor role in the acquisition of phosphorus, especially if there is al imited supplyo fp hosphate. [13,14] Due to their diverse roles, PAPs have attracted attention either as targetsf or new treatments of osteoporosis or for applicationsi na griculture to aid nutrient uptake by crops. [11,15] PAPs operate optimally in the pH range between5 .0 and 6.5, and are characterized by ad istinct purple color due to ac harge-transfer transition between an active-site tyrosine ligand and an Fe III ion. [16,17] The crystal structures of several mammalian and plant PAPs have demonstrated that, despite the difference in the metal ion selectivity and the limited degree of sequence similarity,t heir actives ite geometries are highly conserved (Figure1). [18][19][20][21][22][23] Consequently,t he proposed mod...

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Catalytic Mechanisms of Metallohydrolases Containing Two Metal Ions

Cited by 66 publications

References 155 publications

Kinetic, mechanistic, structural and spectroscopic investigations of Bimetallic Metallohydrolases

Kinetic, mechanistic, structural and spectroscopic investigations of Bimetallic Metallohydrolases

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

The Binding Mode of an ADP Analogue to a Metallohydrolase Mimics the Likely Transition State

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