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

Wells, GA; Birkholtz, Lyn‐Marié; Joubert, Fourie; Walter, Rolf D.; Louw, Abraham I.

doi:10.1016/j.jmgm.2005.09.011

Cited by 19 publications

(27 citation statements)

References 45 publications

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“…This correlates well with what has been predicted in the homology model of PfAdoMetDC [11] and dimeric human AdoMetDC, which showed a minimum at 218 nm and a maximum at 195 nm [23]. It is conceivable that parasite-specific inserts of unknown structure (constituting 32% of the 572-residue PfAdoMetDC protein [11]), contribute to the differences in the spectra with 34% of the PfAdoMetDC secondary structure indicated to be disordered with far-UV CD (Fig. 4).…”

Section: Far-uv CD Analyses Of Pfadometdcsupporting

confidence: 88%

“…Synonymous codons were chosen to ensure that the positional codon frequency of low/intermediate and high usage codons are similar to the frequency used by that of the E. coli host [17]. Codon-harmonised nucleotides 1-1461 (GeneArt, Regensburg, Germany) encoding the core of PfAdoMetDC (487 residues) [11] [9]), which encodes half of the hinge region (wtPfAdoMetDC-hinge, 660 residues) with an N-terminal Strep-tag. In addition, expression of the full-length PfAdoMetDC/ODC proteins from the pASK-IBA3 constructs containing harmA/wtO and wtA/wtO [8] were also compared.…”

Section: Pfadometdc/odcmentioning

confidence: 99%

“…Inspection of the proposed dimer interface of the PfAdoMetDC homology model [11], suggests that Cys505 from each monomer could form a disulphide bond. Therefore, the MALDI-MS peptide mass fingerprints of the dimeric PfAdoMetDC protein (Fig.…”

Section: Involvement Of Cys505 In Disulphide-linked Dimerisation Of Pmentioning

confidence: 99%

“…Processing results in the simultaneous formation of the active site pyruvoyl cofactor at Ser68 [16]. In the case of plasmodial AdoMetDC, homology models predicted a similar α/β-fold to that of the human protein for the monofunctional PfAdoMetDC [11] but other properties e.g. oligomeric status or catalytic mechanism were not elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…Both of these decarboxylase activities function independently of each other within the bifunctional complex [9], although it was shown that inter-and intradomain interactions modulate both activities [10]. In contrast to their single-enzyme orthologues in other organisms, the PfODC activity in the bifunctional enzyme is strongly feedback-inhibited by putrescine, whereas PfAdoMetDC activity is not stimulated by putrescine [9,11]. In the absence of known regulatory mechanisms that control polyamine levels in other organisms, the presence of a single PfAdoMetDC/ODC polypeptide has been suggested to allow regulation of polyamine pools in plasmodia [9].…”

Section: Introductionmentioning

confidence: 99%

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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: Far-uv CD Analyses Of Pfadometdcsupporting

confidence: 88%

Section: Pfadometdc/odcmentioning

confidence: 99%

Section: Involvement Of Cys505 In Disulphide-linked Dimerisation Of Pmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Polyamines in Apicomplexan Parasites

Müller¹,

Gupta²,

Lüersen³

et al. 2011

Apicomplexan Parasites

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Estimating quality of template‐based protein models by alignment stability

Chen

2007

Proteins

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The error in protein tertiary structure prediction is unavoidable, but it is not explicitly shown in most of the current prediction algorithms. Estimated error of a predicted structure is crucial information for experimental biologists to use the prediction model for design and interpretation of experiments. Here, we propose a method to estimate errors in predicted structures based on the stability of the optimal target-template alignment when compared with a set of suboptimal alignments. The stability of the optimal alignment is quantified by an index named the SuboPtimal Alignment Diversity (SPAD). We implemented SPAD in a profile-based threading algorithm and investigated how well SPAD can indicate errors in threading models using a large benchmark dataset of 5232 alignments. SPAD shows a very good correlation not only to alignment shift errors but also structure-level errors, the root mean square deviation (RMSD) of predicted structure models to the native structures (i.e. global errors), and local errors at each residue position. We have further compared SPAD with seven other quality measures, six from sequence alignment-based measures and one atomic statistical potential, discrete optimized protein energy (DOPE), in terms of the correlation coefficient to the global and local structure-level errors. In terms of the correlation to the RMSD of structure models, when a target and a template are in the same SCOP family, the sequence identity showed a best correlation to the RMSD; in the superfamily level, SPAD was the best; and in the fold level, DOPE was best. However, in a head-to-head comparison, SPAD wins over the other measures. Next, SPAD is compared with three other measures of local errors. In this comparison, SPAD was best in all of the family, the superfamily and the fold levels. Using the discovered correlation, we have also predicted the global and local error of our predicted structures of CASP7 targets by the SPAD. Finally, we proposed a sausage representation of predicted tertiary structures which intuitively indicate the predicted structure and the estimated error range of the structure simultaneously.

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

Cited by 19 publications

References 45 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

Polyamines in Apicomplexan Parasites

Estimating quality of template‐based protein models by alignment stability

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