Structural biology of S-adenosylmethionine decarboxylase

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.
Amino Acids (Impact Factor: 3.29). 12/2009; 38(2):451-60. DOI: 10.1007/s00726-009-0404-y
Source: PubMed


S-adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and a subject of many structural and biochemical investigations for anti-cancer and anti-parasitic therapy. The enzyme undergoes an internal serinolysis reaction as a post-translational modification to generate the active site pyruvoyl group for the decarboxylation process. The crystal structures of AdoMetDC from Homo sapiens, Solanum tuberosum, Thermotoga maritima, and Aquifex aeolicus have been determined. Numerous crystal structures of human AdoMetDC and mutants have provided insights into the mechanism of autoprocessing, putrescine activation, substrate specificity, and inhibitor design to the enzyme. The comparison of the human and potato enzyme with the T. maritima and A. aeolicus enzymes supports the hypothesis that the eukaryotic enzymes evolved by gene duplication and fusion. The residues implicated in processing and activity are structurally conserved in all forms of the enzyme, suggesting a divergent evolution of AdoMetDC.

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    • "To become active, the proenzyme undergoes an internal serinolysis, which causes cleavage of the proenzyme into two subunits (α and β) and also results in the formation of a pyruvoyl group at the N-terminus of the α-subunit (Fig. 4a) [62]. In mammals and yeast, Put stimulates AdoMetDC self-processing and activation [63] [64] [65]. "
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    ABSTRACT: The polyamines (PAs) spermidine, spermine, putrescine and cadaverine are an essential class of metabolites found throughout all kingdoms of life. In this comprehensive review, we discuss their metabolism, their various intracellular functions and their unusual and conserved regulatory features. These include the regulation of translation via upstream open reading frames, the over-reading of stop codons via ribosomal frameshifting, the existence of an antizyme and an antizyme inhibitor, ubiquitin-independent proteasomal degradation, a complex bi-directional membrane transport system and a unique posttranslational modification—hypusination—that is believed to occur on a single protein only (eIF-5A). Many of these features are broadly conserved indicating that PA metabolism is both concentration critical and evolutionary ancient. When PA metabolism is disrupted, a plethora of cellular processes are affected, including transcription, translation, gene expression regulation, autophagy and stress resistance. As a result, the role of PAs has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer. Despite comprehensive studies addressing PAs, a unifying concept to interpret their molecular role is missing. The precise biochemical function of polyamines is thus one of the remaining mysteries of molecular cell biology.
    Journal of Molecular Biology 07/2015; · 4.33 Impact Factor
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    • "AdoMetDC catalyzes the conversion of S-adenosylmethionine (AdoMet) to S-adenosyl-5′-(3-methylthiopropylamine), as an early step in the polyamine biosynthetic pathway [6], [10]–[12]. Many bacteria or chlamydial strains have arginine decarboxylase (ArgDC) that converts L-arginine to agmatine [6], [13]–[15], used for a variety of metabolic or defensive purposes against host innate immune responses [16]. The histidine decarboxylation pathway consists of histidine decarboxylase (HisDC) that removes the α-carboxylate group of histidine, which causes histamine spoilage of traditionally fermented foods in food-borne bacteria, such as cheese and wine [14], [17]–[19]. "
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    ABSTRACT: Most of pyruvoyl-dependent proteins observed in prokaryotes and eukaryotes are critical regulatory enzymes, which are primary targets of inhibitors for anti-cancer and anti-parasitic therapy. These proteins undergo an autocatalytic, intramolecular self-cleavage reaction in which a covalently bound pyruvoyl group is generated on a conserved serine residue. Traditional detections of the modified serine sites are performed by experimental approaches, which are often labor-intensive and time-consuming. In this study, we initiated in an attempt for the computational predictions of such serine sites with Feature Selection based on a Random Forest. Since only a small number of experimentally verified pyruvoyl-modified proteins are collected in the protein database at its current version, we only used a small dataset in this study. After removing proteins with sequence identities >60%, a non-redundant dataset was generated and was used, which contained only 46 proteins, with one pyruvoyl serine site for each protein. Several types of features were considered in our method including PSSM conservation scores, disorders, secondary structures, solvent accessibilities, amino acid factors and amino acid occurrence frequencies. As a result, a pretty good performance was achieved in our dataset. The best 100.00% accuracy and 1.0000 MCC value were obtained from the training dataset, and 93.75% accuracy and 0.8441 MCC value from the testing dataset. The optimal feature set contained 9 features. Analysis of the optimal feature set indicated the important roles of some specific features in determining the pyruvoyl-group-serine sites, which were consistent with several results of earlier experimental studies. These selected features may shed some light on the in-depth understanding of the mechanism of the post-translational self-maturation process, providing guidelines for experimental validation. Future work should be made as more pyruvoyl-modified proteins are found and the method should be evaluated on larger datasets. At last, the predicting software can be downloaded from
    PLoS ONE 06/2013; 8(6):e66678. DOI:10.1371/journal.pone.0066678 · 3.23 Impact Factor
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    • "Fusion of the aminopropyltransferase to AdoMetDC creates a problem because a side activity of AdoMetDC results eventually in irreversible transamidation of the AdoMetDC pyruvoyl cofactor, effectively killing the enzyme. The human AdoMetDC pyruvoyl group has been calculated to be transamidated after 15,000 turnover events (Bale & Ealick, 2010). Because of the transamidation, AdoMetDC has a relatively short activity half-life and so has to be synthesized at a relatively high rate. "
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    ABSTRACT: We have identified gene fusions of polyamine biosynthetic enzymes S-adenosylmethionine decarboxylase (AdoMetDC, speD) and aminopropyltransferase (speE) orthologues in diverse bacterial phyla. Both domains are functionally active and we demonstrate the novel de novo synthesis of the triamine spermidine from the diamine putrescine by fusion enzymes from β-proteobacterium Delftia acidovorans and δ-proteobacterium Syntrophus aciditrophicus, in a ΔspeDE gene deletion strain of Salmonella enterica sv. Typhimurium. Fusion proteins from marine α-proteobacterium Candidatus Pelagibacter ubique, actinobacterium Nocardia farcinica, chlorobi species Chloroherpeton thalassium, and β-proteobacterium D. acidovorans each produce a different profile of non-native polyamines including sym-norspermidine when expressed in Escherichia coli. The different aminopropyltransferase activities together with phylogenetic analysis confirm independent evolutionary origins for some fusions. Comparative genomic analysis strongly indicates that gene fusions arose by merger of adjacent open reading frames. Independent fusion events, and horizontal and vertical gene transfer contributed to the scattered phyletic distribution of the gene fusions. Surprisingly, expression of fusion genes in E. coli and S. Typhimurium revealed novel latent spermidine catabolic activity producing non-native 1,3-diaminopropane in these species. We have also identified fusions of polyamine biosynthetic enzymes agmatine deiminase and N-carbamoylputrescine amidohydrolase in archaea, and of S-adenosylmethionine decarboxylase and ornithine decarboxylase in the single-celled green alga Micromonas.
    Molecular Microbiology 08/2011; 81(4):1109-24. DOI:10.1111/j.1365-2958.2011.07757.x · 4.42 Impact Factor
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