Structural analysis by x-ray crystallography of enzymes involved in de novo biosynthesis of pteridines cofactors and vitamins from gtp - the dihydroneopterin aldolase

Objective

Research objectives and content
The three-dimensional structure of the recombinant DHNA enzyme will be determined by protein X-ray crystallography. DHNA from E. Coli is a homooctamer with 123 amino acids and one Zn atom (anomalous scatter) per monomer. The enzyme cleaves a two-carbon segment from D-dihydroneopterin in an early step of folic acid biosynthesis. Folic acid derivatives serve as one-carbon donors in a wide variety of cellular reactions. Crystals of the protein diffracting to 2.1 A resolution have been already obtained by the applicant The structure will be solved using multiple wavelength anomalous dispersion (MAD) for phasing. Solvent flattening and molecular averaging will be important in Phase improvement. The refinement of the model structure will be done using least squares methods and fast fourier transform (FFT ) method.
The DHNA structure will help us to understand the fascinating biochemistry of pteridines and will be followed by inhibitory and mechanistic studies. Training content (objective, benefit and expected impact)
The objective of this training is to solve the structure of DHNA (dihydroneopterin aldolase). This is a new structure and will allow me to get further knowledge in the MIR techniques in which the host group has extensive experience, and in MAD techniques. The result of the investigation can have high impact in the design of a new generation of antibiotics that will inhibit DHNA.
Links with industry / industrial relevance (22)
Currently, links with the pharmaceutical industry do not exist but DHNA is potentially a very attractive target for new antibiotics against bacterial and parasitic diseases.

Fields of science

• natural sciences › earth and related environmental sciences › geology › mineralogy › crystallography
• medical and health sciences › basic medicine › pharmacology and pharmacy › pharmaceutical drugs › antibiotics
• natural sciences › chemical sciences › organic chemistry › amines
• natural sciences › biological sciences › biochemistry › biomolecules › proteins › enzymes

Programme(s)

• FP4-TMR - Specific research and technological development programme in the field of the training and mobility of researchers, 1994-1998

Topic(s)

• 0302 - Post-doctoral research training grants
• TL02 - Molecular Biology and Biochemistry

Call for proposal

Data not available

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.

Address

18a,am Klopferspitz 18a
82152 Planegg / Krailling
Germany

Participants (1)

Not available

Spain