The Structural Basis for Substrate Specificity and Inhibition of Human S-Adenosylmethionine Decarboxylase

Tolbert, W. David; Ekstrom, J.L.; Mathews, I.I.; Secrist, John A.; Kapoor, Preeti; Pegg, Anthony E.; Ealick, S.E.

doi:10.1021/bi015144k

Cited by 16 publications

(54 citation statements)

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“…6D), which is similar to the reported value for wtPfAdoMetDC-hinge (Table 2) [7]. The inhibition of T. cruzi AdoMetDC by CGP48664 was also shown to be non-competitive [31] but inhibition of human AdoMetDC with CGP48664 is competitive [32].…”

Section: Kinetic Analysis Of the Inhibition Of Pfadometdc With Cgp486supporting

confidence: 86%

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

Williams

Sprenger

Human

et al. 2011

Molecular and Biochemical Parasitology

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Plasmodium falciparum like other organisms is dependent on polyamines for proliferation.Polyamine biosynthesis in these parasites is regulated by a unique bifunctional Sadenosylmethionine decarboxylase/ornithine decarboxylase (PfAdoMetDC/ODC). Only limited biochemical and structural information is available on the bifunctional enzyme due to the low levels and impurity of an instable recombinantly expressed protein from the native gene. Here we describe the high level expression of stable monofunctional PfAdoMetDC from a codon-harmonised construct, which permitted its biochemical characterisation indicating similar catalytic properties to AdoMetDCs of orthologous parasites. In the absence of structural data, far-UV CD showed that at least on secondary structure level, PfAdoMetDC corresponds well to that of the human protein. The kinetic properties of the monofunctional enzyme were also found to be different from that of PfAdoMetDC/ODC as mainly evidenced by an increased K m . We deduced that complex formation of PfAdoMetDC and PfODC could enable coordinated modulation of the decarboxylase activities since there is a convergence of their k cat and lowering of their K m . Such coordination results in the aligned production of decarboxylated AdoMet and putrescine for the subsequent synthesis of spermidine. Furthermore, based on the results obtained in this study we propose a new AdoMetDC subclass for plasmodial AdoMetDCs.

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Section: Kinetic Analysis Of the Inhibition Of Pfadometdc With Cgp486supporting

confidence: 86%

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

Williams

Sprenger

Human

et al. 2011

Molecular and Biochemical Parasitology

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“…The combination of length and charge A. [113]. Putrescine binding reorients hydrophilic residues through the center of the enzyme, opening the active site.…”

Section: Polyamine Interactionsmentioning

confidence: 99%

Autoimmune Diseases and Polyamines

Brooks

2011

Clinic Rev Allerg Immunol

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Genetics and environmental factors have important roles in autoimmune diseases but neither has given us sufficient understanding of these mysterious diseases. Therefore, we are now looking closer at epigenetics, an interface between genetics and environmental factors. Epigenetics can be defined as reversible heritable changes to chromatin that can alter gene expression without altering the gene's DNA sequence. Methylation of DNA and histones are primary means of epigenetic control. By adding methyl groups to DNA and histones, it can limit accessibility of the underlying gene thereby altering the amount of gene expression. The methyl group is derived from an essential molecule in the cell, S-adenosylmethionine (SAM). However, a group of small molecules called polyamines also require SAM for their synthesis. Polyamines are essential for many cellular functions and polyamine activity is increased in many autoimmune diseases. Presented here is the "polyamine hypothesis" in which increased polyamine synthesis competes with cellular methylation (epigenetic control) for SAM. It is proposed that increased polyamine activity can cause disruption of cellular methylation, which can lead to abnormal expression of previously sequestered genes and disruption of other methylation-dependent cellular processes.

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“…[22]) and the human enzyme irreversibly complexed with the substrate methyl-ester (1.9-2.7 Å , PDB entry 1I7B: Refs. [17,23] were used as templates for homology modeling. Initial models were built with Modeller 6v2 [26][27][28], using a high refinement (refine_4) to generate 100 models.…”

Section: Homology Modelingmentioning

confidence: 99%

“…The adenine ring of MeAdoMet is stacked hydrophobically between the phenyl rings of Phe5 and Phe415, as in the human structure (Phe7 hum and Phe223 hum). Mutagenesis of the human enzyme suggested these residues are important for substrate and inhibitor binding [23]. Glu438, like Glu247 hum, forms two hydrogen bonds with both hydroxyls of the ribose moiety.…”

Section: Active Site Characteristicsmentioning

confidence: 99%

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Novel properties of malarial S-adenosylmethionine decarboxylase as revealed by structural modelling

Wells

Birkholtz

Joubert

et al. 2006

Journal of Molecular Graphics and Modelling

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The Structural Basis for Substrate Specificity and Inhibition of Human S-Adenosylmethionine Decarboxylase

Cited by 16 publications

References 0 publications

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

Autoimmune Diseases and Polyamines

Novel properties of malarial S-adenosylmethionine decarboxylase as revealed by structural modelling

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