1nbu
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7,8-Dihydroneopterin Aldolase Complexed with Product From Mycobacterium Tuberculosis
OverviewOverview
Folate derivatives are essential cofactors in the biosynthesis of purines, pyrimidines and amino acids across all forms of life. Mammals uptake, folate from their diets, whereas most bacteria must synthesize folate de, novo. Therefore, the enzymes in the folate biosynthetic pathway are, attractive drug targets against bacterial pathogens such as Mycobacterium, tuberculosis, the cause of the world's most deadly infectious disease, tuberculosis (TB). M.tuberculosis 7,8-dihydroneopterin aldolase (Mtb FolB, DHNA) is the second enzyme in the folate biosynthetic pathway, which, catalyzes the conversion of 7,8-dihydroneopterin to, 6-hydroxymethyl-7,8-dihydropterin and glycoaldehyde. The 1.6A X-ray, crystal structure of Mtb FolB complexed with its product, 6-hydroxymethyl-7,8-dihydropterin, reveals an octameric assembly similar, to that seen in crystal structures of other FolB homologs. However, the, 2.5A crystal structure of unliganded Mtb FolB reveals a novel tetrameric, oligomerization state, with only partially formed active sites. A, substrate induced conformational change appears to be necessary to convert, the inactive tetramer to the active octamer. Ultracentrifugation confirmed, that in solution unliganded Mtb FolB is mainly tetrameric and upon, addition of substrate FolB is predominantly octameric. Kinetic analysis of, substrate binding gives a Hill coefficient of 2.0, indicating positive, cooperativity. We hypothesize that Mtb FolB displays cooperativity in, substrate binding to regulate the cellular concentration of, 7,8-dihydroneopterin, so that it may function not only as a precursor to, folate but also as an antioxidant for the survival of M.tuberculosis, against host defenses.
About this StructureAbout this Structure
1NBU is a Protein complex structure of sequences from Mycobacterium tuberculosis with PH2 as ligand. Active as Dihydroneopterin aldolase, with EC number 4.1.2.25 Full crystallographic information is available from OCA.
ReferenceReference
Regulation by oligomerization in a mycobacterial folate biosynthetic enzyme., Goulding CW, Apostol MI, Sawaya MR, Phillips M, Parseghian A, Eisenberg D, J Mol Biol. 2005 May 27;349(1):61-72. Epub 2005 Apr 2. PMID:15876368
Page seeded by OCA on Tue Nov 20 22:07:27 2007
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OCA- Pages with broken file links
- Dihydroneopterin aldolase
- Mycobacterium tuberculosis
- Protein complex
- Apostol, M.I.
- Eisenberg, D.
- Goulding, C.W.
- Parseghian, A.
- Phillips, M.
- Sawaya, M.R.
- TBSGC, TB.Structural.Genomics.Consortium.
- PH2
- Anti-parallel
- Beta-sheet
- Protein structure initiative
- Psi
- Structural genomics
- Tb structural genomics consortium
- Tbsgc
- Two alpha helices