Antimalarial activity of a 4', 5'-unsaturated 5'- fluoroadenosine mechanism-based inhibitor of s-adenosyl-l-homocysteine hydrolase

Bitonti, Alan J.; Baumann, Russell J.; Jarvi, Esa T.; McCarthy, James R.; McCann, Peter P.

doi:10.1016/0006-2952(90)90562-y

Cited by 37 publications

(18 citation statements)

References 13 publications

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“…8C). Acetylation of Lys 401 results in a rearrangement of a hydrogen bonding network between Lys 401 , Asn 27 , and Asp 293 (Fig. 8D).…”

Section: Sahh Ackmentioning

confidence: 99%

“…8D). In SAHH AcK 401/408 , the ⑀-amino group of AcK 408 makes hydrogen bonds to the backbone carbonyl of Asn 27 . In the non-acetylated structure, a water mediates this interaction.…”

Section: Sahh Ackmentioning

confidence: 99%

“…It has been established previously that genetic knockdown of SAHH or its chemical inhibition by 3-deazaneplanocin A leads to accumulation of AdoHcy and generalized product inhibition of AdoMet-dependent methyltransferases (2,3). One of the enzymes that seems particularly sensitive to AdoHcy feedback inhibition is EZH2, the histone lysine methyltransferase component of the Polycomb repressor complex 2 responsible for Lys 27 methylation of histone H3, a signature mark of heterochromatic gene silencing (2)(3)(4). Recent studies indicate that SAHH inhibition by 3-deazaneplanocin A can reactivate developmental genes in acute myeloid leukemia cells, halting cellular proliferation (3,4).…”

mentioning

confidence: 99%

“…Whereas SAHH is recognized as a key enzyme in controlling gene expression and a potential drug target for the design of antiviral (25,26), antiparasitic (27), and antiarthritic agents (28), the cellular regulation of SAHH is poorly understood. Several years ago, mammalian SAHH was reported in a proteomics study to be acetylated on two C-terminal Lys resides, 401 and 408 (29), the latter of which is highly conserved.…”

mentioning

confidence: 99%

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Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

Wang¹,

Kavran²,

Chen³

et al. 2014

Journal of Biological Chemistry

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“…8C). Acetylation of Lys 401 results in a rearrangement of a hydrogen bonding network between Lys 401 , Asn 27 , and Asp 293 (Fig. 8D).…”

Section: Sahh Ackmentioning

confidence: 99%

“…8D). In SAHH AcK 401/408 , the ⑀-amino group of AcK 408 makes hydrogen bonds to the backbone carbonyl of Asn 27 . In the non-acetylated structure, a water mediates this interaction.…”

Section: Sahh Ackmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

Wang¹,

Kavran²,

Chen³

et al. 2014

Journal of Biological Chemistry

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“…The genomic approach will generate a database for the population genetics of malaria parasites and contribute to the development of antimalarial paradigms [14]. Since methylation of macromolecules by SAMS has been implicated in the development of organisms or diseases [5,6,15,16], and inhibitors of methylation have been shown to exert antimalarial activity in itro and in i o [6,[17][18][19][20], we describe here a gene coding for SAMS from Plasmodium falciparum (PfSAMS) (GenBank accession no. AF097923), and the characterization of its encoded protein.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of Plasmodium falciparum S-adenosylmethionine synthetase

Chiang

Chamberlin

Nicholson

et al. 1999

Biochemical Journal

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S-Adenosylmethionine (AdoMet) synthetase (SAMS: EC 2.5.1.6) catalyses the formation of AdoMet from methionine and ATP. We have cloned a gene for Plasmodium falciparum AdoMet synthetase (PfSAMS) (GenBank accession no. AF097923), consisting of 1209 base pairs with no introns. The gene encodes a polypeptide (PfSAMS) of 402 amino acids with a molecular mass of 44844 Da, and has an overall base composition of 67% A+T. PfSAMS is probably a single copy gene, and was mapped to chromosome 9. The PfSAMS protein is highly homologous to all other SAMS, including a conserved motif for the phosphate-binding P-loop, HGGGAFSGKD, and the signature hexapeptide, GAGDQG. All the active-site amino acids for the binding of ADP, Pi and metal ions are similarly preserved, matching entirely those of human hepatic SAMS and Escherichia coli SAMS. Molecular modelling of PfSAMS guided by the X-ray crystal structure of E. coli SAMS indicates that PfSAMS binds ATP/Mg2+ in a manner similar to that seen in the E. coli SAMS structure. However, the PfSAMS model shows that it can not form tetramers as does E. coli SAMS, and is probably a dimer instead. There was a differential sensitivity towards the inhibition by cycloleucine between the expressed PfSAMS and the human hepatic SAMS with Ki values of 17 and 10 mM, respectively. Based on phylogenetic analysis using protein parsimony and neighbour-joining algorithms, the malarial PfSAMS is closely related to SAMS of other protozoans and plants.

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The IRBIT domain adds new functions to the AHCY family

2008

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SummaryDuring the past few years, the IRBIT domain has emerged as an important add-on of S-adenosyl-L-homocystein hydrolase (AHCY), thereby creating the new family of AHCY-like proteins. In this review, we discuss the currently available data on this new family of proteins. We describe the IRBIT domain as a unique part of these proteins and give an overview of its regulation via (de)phosphorylation and proteolysis. The second part of this review is focused on the potential functions of the AHCY-like proteins. We propose that the IRBIT domain serves as an anchor for targeting AHCY-like proteins towards cytoplasmic targets. This leads to regulation of (i) The AHCY family AHCY S-adenosyl-L-homocystein (SAH) hydrolase (AHCY) is a ubiquitous, tetrameric enzyme that catalyzes the reversible hydrolysis of SAH to adenosine and L-homocysteine. SAH is formed as a by-product of S-adenosyl-L-methionine (SAM) through transmethylation reactions. The hydrolysis of SAH is required to maintain low cellular concentrations of SAH, which is a product inhibitor of S-adenosyl-L-methionine (SAM)-dependent transmethylation reactions.(1-4) Inhibition of AHCY results in the intracellular accumulation of SAH, causing a significant increase in the intracellular SAH/SAM ratio and the subsequent inhibition of SAM-dependent methylations.( 5 -8) SAM is the major methyl donor for delivery of methyl groups to DNA, RNA, proteins and cellular metabolites in eukaryotes and SAH hydrolysis is the only source of homocysteine in mammals.(9) AHCY has become an attractive target for design of broad-spectrum antiviral agents because of the inhibitory effects of elevated intracellular SAH concentrations on viral mRNA cap-methylating enzymes. (10,11) In addition to these antiviral effects, AHCY inhibitors have also been attributed antiparasitic, (12,13) anti-arthritic (14) and immunosuppressive (15) effects.The importance of AHCY for mammalian survival is suggested by the fact that a chromosomal deletion that includes the gene encoding AHCY causes embryonic lethality in mice.(16) Elevated homocysteine levels have been reported as a risk factor for dementia and Alzheimer's disease, (17) and as a possible risk marker for vascular disease. (18,19) Human AHCY deficiency, such as in hypermethionemia, results in severe biochemical abnormalities, including plasma elevations of 150-fold in SAH, 30-fold in SAM and 12-fold in methionine. (20,21) So far, three mutations in the AHCY gene have been found to reduce the activity of the AHCY enzyme, resulting in the signs and symptoms of hypermethionemia. (22,23) AHCY orthologues have been identified in many species, including bacteria, nematodes, yeast, plants, insects and vertebrates. In contrast, the AHCY-like (AHCYL) family members AHCYL1 (also termed IRBIT, the inositol 1,4, 5-trisphosphate (IP 3 ) receptor (IP 3 R) binding protein released by IP 3 ) and AHCYL2 (KIAA0828 in human) are only predicted in segmented multicellular organisms, like vertebrates (eg Takifugu rubripes (fugu fish), Danio rerio (zebrafish), Xen...

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Antimalarial activity of a 4', 5'-unsaturated 5'- fluoroadenosine mechanism-based inhibitor of s-adenosyl-l-homocysteine hydrolase

Cited by 37 publications

References 13 publications

Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

Molecular characterization of Plasmodium falciparum S-adenosylmethionine synthetase

The IRBIT domain adds new functions to the AHCY family

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