Protein Name

Nicotinamide phosphoribosyltransferase (NMPRTase): Complex with FK866



Biological Context

NAD+ is an important molecule which works as an oxidation-reduction reaction agent in various biochemical reactions. A common feature of these biochemical reactions is that the glycosidic bond between nicotinamide (NM) and ribose gets broken, destroying the parent NAD+ and releasing a free nicotinamide (NM). Through the salvage pathway, NMPRTase (nicotinamide phosphoribosyltransferase) synthesizes nicotinamide nucleotide (NMN) from nicotinamide (NM), and it lead to the increase of intracellular NAD+ concentration. On the other hand, it is identified that tumor cells have a high rate of NAD+ concentration owing to elevated NMPRTase expression. Therefore inhibitors of NMPRTase are expected as anticancer agents. Moreover, two kinds of enzymes with the same function as NMPRTase exist. They are NAPRTase (nicotine acid phosphoribosyltransferase) and QAPRTase (quinoline acid phosphoribosyltransferase), and they biosynthesize NAD+ from nicotinic acid (NA) and quinolinic acid (QA), respectively. Although the sequence identity between these enzymes is not high, their structures are similar.

Structure Description


The structure shown here is the complex of NMPRTase and its inhibitor, FK866. The monomer of NMPRTase consists of 22 beta-strands and 15 alpha-helices, and is divided into three domains: A domain, B domain, and C domain. (Fig.1) Moreover, it is recognized that this enzyme expresses its catalytic activity as a dimer. Two monomers are arranged head to tail, with the A domain in one monomer contacting the B domain in the other monomer. (Fig.2). The active site is located near the tip of the central beta sheet of the B domain. This region is just located in the interface of the dimer of NMPRTase. The amide ring of FK866 has interaction with Phe193, Asp219, Arg311, and Tyr18' which supplied from the other chain (Fig.3).

There are two main features specific to NMPRTase. First, about a ten-residue loop (234-243) is inserted between α8 (8th α-helix) and β8 (8th β-strand). Some amino acids in β8 have direct interactions with the substrate (NA or QA) in other two enzymes. On the other hand, some amino acids of beta 8 are kept away from the active site because of inserted loop, and do not have interactions with the substrate (NM) in NMPRTase. Next, although Asp219 NMPRTase forms the hydrogen bond to amide ring of NM, this interaction does not exist in other two enzymes. Asp219 has a negative charge and should block an NA molecule from approaching the active site. According to a mutation experiment, when Asp219 is replaced by another residue, NMPRTase showed catalytic activity not only to NM, but also to NA. It is suggested that these two features contribute to the substrate specificity of NMPRTase greatly. Moreover, there is a tunnel connected with active site exists in the interface of dimer. This tunnel is very narrow ; 15A x 6A (length x diameter). FK866 is of a thin form in accordance with this tunnel, and it is possible to function as a inhibitor which may block the active site of NMPRTase.

closeup closeup
(Fig.1) Monomer (Fig.2) Dimer
(Fig.3) Active site

Protein Data Bank (PDB)



  • Khan, J.A. Tao, X. Tong, L.; "Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents."; Nat.Struct.Mol.Biol.; (2006) 13:582-588 PubMed:16783377.


author: Jun-ichi Ito

Japanese version:PDB:2GVJ