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Structural biology of S-adenosylmethionine decarboxylase

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Abstract

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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Abbreviations

AdoMetDC:

S-adenosylmethionine decarboxylase

dcAdoMet:

S-adenosyl-5′-(3-methylthiopropylamine)

AdoMet:

S-adenosylmethionine

MeAdoMet:

S-adenosylmethionine methyl ester

hAdoMetDC:

Human AdoMetDC

pAdoMetDC:

Potato AdoMetDC

TmAdoMetDC:

Thermotoga maritima AdoMetDC

ODC:

Ornithine decarboxylase

MGBG:

Methylglyoxal bis(guanylhydrazone)

CGP48664A:

4-Amidinoindan-1-one-2′-amidinohydrazone

MMTA:

5′-Deoxy-5′-(dimethylsulfonio)adenosine

DMAMA:

5′-Deoxy-5′-(N-dimethyl)amino-8-methyl adenosine

MHZPA:

5′-Deoxy-5′-[N-methyl-N-(3-hydrazinopropyl)amino]adenosine

MAOEA:

5′-Deoxy-5′-[N-methyl-N-[(2-aminooxy)ethyl]amino]adenosine

TbAdoMetDC:

Trypanosomabrucei AdoMetDC

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Acknowledgments

We thank Ms. Leslie Kinsland for assistance in the preparation of this manuscript. This work was supported by National Institutes of Health Grant CA-94000.

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  1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA

    Shridhar Bale & Steven E. Ealick

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  1. Shridhar Bale
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Correspondence to Steven E. Ealick.

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Bale, S., Ealick, S.E. Structural biology of S-adenosylmethionine decarboxylase. Amino Acids 38, 451–460 (2010). https://doi.org/10.1007/s00726-009-0404-y

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