PDBsum entry 4zup

Hydrolase/hydrolase inhibitor

PDB id: 4zup

Contents

Protein chains

341 a.a.

Ligands

5XA ×2

GOL ×4

NO3 ×4

Metals

_ZN ×4

__K ×4

Waters ×950

PDB id:

4zup

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of acetylpolyamine amidohydrolase from mycoplana ramosa in complex with a hydroxamate inhibitor

Structure:

Acetylpolyamine aminohydrolase. Chain: a, b. Engineered: yes

Source:

Mycoplana ramosa. Organism_taxid: 40837. Gene: apha, aph. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.42Å R-factor: 0.132 R-free: 0.152

Authors:

C.Decroos,D.W.Christianson

Key ref:

C.Decroos and D.W.Christianson (2015). Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase. Biochemistry, 54, 4692-4703. PubMed id: 26200446 DOI: 10.1021/acs.biochem.5b00536

Date:

17-May-15 Release date: 29-Jul-15

Protein chains

Q48935  (APAH_MYCRA) -  Acetylpolyamine amidohydrolase from Mycoplana ramosa

Seq: 341 a.a.

Struc: 341 a.a.

Enzyme reactions

• Enzyme class 1: E.C.3.5.1.- - ?????
• Enzyme class 2: E.C.3.5.1.48 - acetylspermidine deacetylase.
• Reaction: N₈-acetylspermidine + H2O = spermidine + acetate

N(8)-acetylspermidine + H2O = spermidine (Bound ligand (Het Group name = GOL) matches with 42.86% similarity) + acetate (Bound ligand (Het Group name = 5XA) matches with 50.00% similarity)

• Enzyme class 3: E.C.3.5.1.62 - acetylputrescine deacetylase.
• Reaction: N-acetylputrescine + H2O = putrescine + acetate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.biochem.5b00536

Biochemistry 54:4692-4703 (2015)

PubMed id: 26200446

Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase.

C.Decroos, D.W.Christianson.

ABSTRACT

Polyamines are essential aliphatic polycations that bind to nucleic acids and accordingly are involved in a variety of cellular processes. Polyamine function can be regulated by acetylation and deacetylation, just as histone function can be regulated by lysine acetylation and deacetylation. Acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa is a zinc-dependent polyamine deacetylase that shares approximately 20% amino acid sequence identity with human histone deacetylases. We now report the X-ray crystal structures of APAH-inhibitor complexes in a new and superior crystal form that diffracts to very high resolution (1.1-1.4 Å). Inhibitors include previously synthesized analogues of N(8)-acetylspermidine bearing trifluoromethylketone, thiol, and hydroxamate zinc-binding groups [Decroos, C., Bowman, C. M., and Christianson, D. W. (2013) Bioorg. Med. Chem. 21, 4530], and newly synthesized hydroxamate analogues of shorter, monoacetylated diamines, the most potent of which is the hydroxamate analogue of N-acetylcadaverine (IC50 = 68 nM). The high-resolution crystal structures of APAH-inhibitor complexes provide key inferences about the inhibition and catalytic mechanism of zinc-dependent deacetylases. For example, the trifluoromethylketone analogue of N(8)-acetylspermidine binds as a tetrahedral gem-diol that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Surprisingly, this compound is also a potent inhibitor of human histone deacetylase 8 with an IC50 of 260 nM. Crystal structures of APAH-inhibitor complexes are determined at the highest resolution of any currently existing zinc deacetylase structure and thus represent the most accurate reference points for understanding structure-mechanism and structure-inhibition relationships in this critically important enzyme family.