Steve Ealick's Research Group


Human S-Adenosylmethionine Decarboxylase


PDB files:

1JEN (with pyruvoyl group)

1I72* (with covalently bound pyruvoyl group and covalently bound 5′-deoxy-5′-[N-methyl-N-(2-aminooxyethyl) amino]adenosine; MAOEA)

1I7B* (with covalently bound pyruvoyl group and covalently bound S-adenosylmethionine methyl ester; MeAdoMet)

1I7C* (with covalently bound pyruvoyl group and complexed with methylglyoxal bis-(guanylhydrazone; MGBG)

1I79* (with covalently bound pyruvoyl group and covalently bound 5′-deoxy-5′-[(3-hydrazinopropyl)methylamino]adenosine; MHZPA)

1I7M* (with covalently bound pyruvoyl group and complexed with 4-amidinoindan-1-one-2′-amidinohydrazone)

1JL0# (H243A mutant with putrescine, hydroxyalanine, and tris(hydroxymethy)aminomethane)

1MSV1 (S68A mutant with putrescine and 2-amino-2-hydroxymethylpropane-1,3-diol)

3DZ22 with 5′-[(3-aminopropyl)methylamino]-5′-deoxy-8-methyladenosine

3DZ32 F223A mutant with covalently bound S-Adenosylmethionine methyl ester

3DZ42 with 5′-[(2-carboxamidoethyl)methylamino]-5′-deoxy-8-methyladenosine

3DZ52 with covalently bound 5′-[(2-aminooxyethyl)methylamino]-5′-deoxy-8-methyladenosine

3DZ62 with 5′-[(4-aminooxybutyl)methylamino]-5′-deoxy-8-ethyladenosine

3DZ72 with 5′-[(carboxamidomethyl)methylamino]-5′-deoxy-8-methyladenosine

3EP33 (D174N mutant with no putrescine)

3EP43 (E256Q mutant with no putrescine)

3EP53 (E178Q mutant with no putrescine)

3EP63 (D174N mutant with no putrescine complexed with MeAdoMet)

3EP73 (E256Q mutant with no putrescine complexed with MeAdoMet)

3EP83 (E178Q mutant with no putrescine complexed with MeAdoMet)

3EP93 (native with no putrescine bound)

3EPA3 (E178Q mutant with putrescine)

3EPB3 (E256Q mutant with putrescine)

3H0V4 (complexed with 5´-deoxy-5´-(dimethylsulfonio)adenosine (MMTA))

3H0W4 (complexed with 5´-deoxy-5´-(N-dimethyl)amino-8-methyladenosine (DMAMA))

Description:

S-Adenosylmethionine Decarboxylase (AdoMetDC) is a critical regulatory enzyme in the polyamine synthetic pathway, and is a target of drug design. AdoMetDC catalyzes the removal of the carboxylate group from S-adenosylmethionine (AdoMet) to form S-adenosyl-5′-3-methylthiopropylamine. This acts as the n-propylamine donor to synthesize spermidine and spermine from putrescine.

The monomer consists of structurally similar halves, indicating ancient gene-duplication.

 

Click the image to enlarge.

 

The active form of AdoMetDC is an (αβ)2 dimer, with the active site (catalytic pyruvoyl residue) located far from the dimer interface. The architecture of the αβ monomer is a novel α/β sandwich fold, comprised of two antiparallel eight-strandedβ sheets flanked by several α and 310 helices.

Click the image to enlarge.

The proposed active site cavity is open to solvent on one side and positioned between the two topologically equivalent halves in an arrangement analogous to the location of active sites at domain interfaces. The residues facing this cavity are shown in this diagram of the active site *.

References:

Ekstrom JL, Mathews II, Stanley BA, Pegg AE, and Ealick SE. The Crystal Structure of Human S-Adenosylmethionine Decarboxylase at 2.25 Å Resolution Reveals a Novel Fold. Structure 7:583-595 (1999).

#Ekstrom JL, Tolbert WD, Xiong H, Pegg AE, and Ealick SE. The Crystal Structure of the H243A Mutant of S-Adenosylmethionine Decarboxylase at 1.5 Å Resolution Reveals a Proenzyme Ester Intermediate. Biochemistry 40:9495-9504 (2001).

*Tolbert WD, Ekstrom JL, Mathews II, Secrist JA III, Kapoor P, Pegg AE, and Ealick SE. The Structural Basis for Substrate Specificity and Inhibition of Human S-Adenosylmethionine Decarboxylase. Biochemistry 40:9484-9494 (2001).

1Tolbert WD, Zhang Y, Cottet SE, Bennett EM, Ekstrom JL, Pegg AE, and Ealick SE. Mechanism of Human S-Adenosylmethionine Decarboxylase Proenzyme Processing as Revealed by the Structure of the S68A Mutant. Biochemistry 42:2386-2395 (2003).

2 McCloskey DE, Bale S, Secrist JA III, Tiwari A, Moss TH III, Valiyaveettil J, Brooks W, Guida WC, Pegg AE, and Ealick SE. New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C8 Substitution in Structural Analogues of S-Adenosylmethionine. J. Med. Chem. 52:1388-1407 (2009).

3Bale S, Lopez MM, Makhatadze G; Fang QI; Pegg AE, and Ealick SE. Structural Basis for Putrescine Activation of Human S-Adenosylmethionine Decarboxylase. Biochemistry 47: 13404-13417 (2008).

4Bale S, Guida WC, Brooks WH, Hanes JW, Mahesan AM and Ealick SE. Role of the Sulfonium Center in Determining Ligand Specificity of Human S-Adenosylmethionine Decarboxylase. Biochemistry 48:6423-6430 (2009).



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