PDBsum entry 5a6h

Lyase

PDB id: 5a6h

Contents

Protein chain

259 a.a.

Ligands

DMS

OE2 ×3

Metals

_ZN

Waters ×274

PDB id:

5a6h

Name:

Lyase

Title:

Synthesis, carbonic anhydrase inhibition and protein x-ray structure of the unusual natural product primary sulfonamide psammaplin c

Structure:

Carbonic anhydrase 2. Chain: a. Synonym: carbonate dehydratase ii, carbonic anhydrasE C, cac, carbonic anhydrase ii, ca-ii, human carbonic anhydrase ii. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.57Å R-factor: 0.148 R-free: 0.193

Authors:

P.Mujumdar,C.T.Supuran,T.S.Peat,S.Poulsen

Key ref:

P.Mujumdar et al. (2016). An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C. J Med Chem, 59, 5462-5470. PubMed id: 27172398 DOI: 10.1021/acs.jmedchem.6b00443

Date:

26-Jun-15 Release date: 25-May-16

Protein chain

P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2 from Homo sapiens

Seq: 260 a.a.

Struc: 259 a.a.

Enzyme reactions

• Enzyme class 2: E.C.4.2.1.1 - carbonic anhydrase.
• Reaction: hydrogencarbonate + H⁺ = CO2 + H2O
• Cofactor: Zn(2+)
• Enzyme class 3: E.C.4.2.1.69 - cyanamide hydratase.
• Reaction: urea = cyanamide + H2O

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.jmedchem.6b00443

J Med Chem 59:5462-5470 (2016)

PubMed id: 27172398

An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C.

P.Mujumdar, K.Teruya, K.F.Tonissen, D.Vullo, C.T.Supuran, T.S.Peat, S.A.Poulsen.

ABSTRACT

Psammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs.