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1. WO2007145539 - CRYSTAL STRUCTURE OF A SUBSTRATE COMPLEX OF MIOX

Publication Number WO/2007/145539
Publication Date 21.12.2007
International Application No. PCT/NZ2007/000154
International Filing Date 14.06.2007
IPC
C12N 9/02 2006.1
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9Enzymes, e.g. ligases (6.); Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating, or purifying enzymes
02Oxidoreductases (1.), e.g. luciferase
A61P 3/10 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
3Drugs for disorders of the metabolism
08for glucose homeostasis
10for hyperglycaemia, e.g. antidiabetics
G06Q 50/00 2006.1
GPHYSICS
06COMPUTING; CALCULATING OR COUNTING
QDATA PROCESSING SYSTEMS OR METHODS, SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL, SUPERVISORY OR FORECASTING PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL, SUPERVISORY OR FORECASTING PURPOSES, NOT OTHERWISE PROVIDED FOR
50Systems or methods specially adapted for specific business sectors, e.g. utilities or tourism
A61K 38/44 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38Medicinal preparations containing peptides
16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
43Enzymes; Proenzymes; Derivatives thereof
44Oxidoreductases (1)
CPC
A61P 3/10
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
3Drugs for disorders of the metabolism
08for glucose homeostasis
10for hyperglycaemia, e.g. antidiabetics
C12N 9/0069
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9Enzymes; Proenzymes; Compositions thereof
0004Oxidoreductases (1.)
0069acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
C12Y 113/99001
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
YENZYMES
113Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13)
99Miscellaneous (1.13.99)
99001Inositol oxygenase (1.13.99.1), i.e. myo-inositol oxygenase
Applicants
  • PROTEMIX DISCOVERY LIMITED [NZ]/[NZ] (AllExceptUS)
  • LOOMES, Kerry, L [NZ]/[NZ] (UsOnly)
  • BROWN, Peter, M [NZ]/[NZ] (UsOnly)
  • CARADOC-DAVIES, Tom, T [NZ]/[NZ] (UsOnly)
  • DICKSON, James [NZ]/[NZ] (UsOnly)
  • COOPER, Garth, J, S [NZ]/[NZ] (UsOnly)
  • BAKER, Edward, N [NZ]/[NZ] (UsOnly)
Inventors
  • LOOMES, Kerry, L
  • BROWN, Peter, M
  • CARADOC-DAVIES, Tom, T
  • DICKSON, James
  • COOPER, Garth, J, S
  • BAKER, Edward, N
Agents
  • ADAMS, Matthew, D.
Priority Data
60/814,41814.06.2006US
Publication Language English (en)
Filing Language English (EN)
Designated States
Title
(EN) CRYSTAL STRUCTURE OF A SUBSTRATE COMPLEX OF MIOX
(FR) structure cristalline d'un complexe substrat de MIOX
Abstract
(EN) Diabetes mellitus is a chronic disease that is associated with altered metabolism of the inositol sugars myo-inositol (MI) and D-chiro-inositol (DCI). In animals, catabolism of MI and DCI depends on the enzyme myo-inositol oxygenase (MIOX), which catalyzes the first committed step of the glucuronate-xylulose pathway, and is found almost exclusively in the kidneys. The crystal structure of MIOX, in complex with MI, has been determined by multiwavelength anomalous diffraction methods and refined at 2.0-A resolution (R = 0.208, Rfree = 0.258). The structure reveals a monomeric, single-domain protein with a mostly-helical fold that is distantly related to the diverse HD domain superfamily. Five helices form the structural core and provide six ligands (4 His and 2 Asp) for the di-iron center, in which the two iron atoms are bridged by a putative hydroxide ion and one of the aspartate ligands, Asp124. A key loop forms a lid over the MI substrate, which is coordinated in bidentate mode to one iron atom. It is proposed that this mode of iron coordination, and interaction with a key lysine residue, activate MI for bond cleavage. The structure also reveals the basis of substrate specificity and suggests routes for the development of specific MIOX inhibitors for treatment of inositol-associated disorders.
(FR) Le diabète sucré est une maladie chronique qui est associée à un métabolisme altéré des sucres inositol, myo-inositol (MI) et D-chiro-inositol (DCI). Chez les animaux, le catabolisme des MI et DCI dépend de l'enzyme myo-inositol oxygénase (MIOX), qui catalyse la première phase engagée du trajet de glucuronate-xylulose, et se trouve pratiquement de manière exclusive dans les reins. La structure cristalline de MIOX, en complexe avec MI, a été déterminée par des procédés de diffraction d'anomalie à multiples longueurs d'ondes et peaufinée pour obtenir une résolution de 2,0-A (R = 0,208, Rfree = 0,258). La structure révèle une protéine de simple domaine, monomère avec un repli pratiquement hélicoïdal étant apparentée de manière distante à la superfamille variée de domaine HD. Cinq hélices constituent le noyau structurel et fournissent six ligands (4 His et 2 Asp) pour le centre di-fer, dans lequel les deux atomes de fer sont pontés par un ion d'hydroxyde putatif et l'un des ligands d'aspartate, Asp124. Une boucle clé forme un couvercle au-dessus du substrat MI, qui est coordonné en mode bidentate à un atome de fer. On propose que ce mode de coordination de fer, et l'interaction avec un résidu lysine clé, activent MI pour le clivage de liaison. La structure révèle également la base de la spécificité de substrat et suggère des perspectives pour le développement d'inhibiteurs MIOX spécifiques pour le traitement de troubles associés à l'inositol.
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