PMID- 10369661
OWN - NLM
STAT- MEDLINE
DCOM- 19990819
LR  - 20181113
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 12
DP  - 1999 Jun 15
TI  - Molecular basis of glutathione synthetase deficiency and a rare gene permutation 
      event.
PG  - 3204-13
AB  - Glutathione synthetase (GS) catalyses the production of glutathione from
      gamma-glutamylcysteine and glycine in an ATP-dependent manner. Malfunctioning of 
      GS results in disorders including metabolic acidosis, 5-oxoprolinuria,
      neurological dysfunction, haemolytic anaemia and in some cases is probably
      lethal. Here we report the crystal structure of human GS (hGS) at 2.1 A
      resolution in complex with ADP, two magnesium ions, a sulfate ion and
      glutathione. The structure indicates that hGS belongs to the recently identified 
      ATP-grasp superfamily, although it displays no detectable sequence identity with 
      other family members including its bacterial counterpart, Escherichia coli GS.
      The difficulty in identifying hGS as a member of the family is due in part to a
      rare gene permutation which has resulted in a circular shift of the conserved
      secondary structure elements in hGS with respect to the other known ATP-grasp
      proteins. Nevertheless, it appears likely that the enzyme shares the same general
      catalytic mechanism as other ligases. The possibility of cyclic permutations
      provides an insight into the evolution of this family and will probably lead to
      the identification of new members. Mutations that lead to GS deficiency have been
      mapped onto the structure, providing a molecular basis for understanding their
      effects.
FAU - Polekhina, G
AU  - Polekhina G
AD  - The Ian Potter Foundation Protein Crystallography Laboratory, St Vincent's
      Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065,
      Australia.
FAU - Board, P G
AU  - Board PG
FAU - Gali, R R
AU  - Gali RR
FAU - Rossjohn, J
AU  - Rossjohn J
FAU - Parker, M W
AU  - Parker MW
LA  - eng
SI  - PDB/2HGS
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Phosphates)
RN  - 0 (Sulfates)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 6.3.2.3 (Glutathione Synthase)
RN  - GAN16C9B8O (Glutathione)
RN  - I38ZP9992A (Magnesium)
SB  - IM
MH  - Adenosine Diphosphate/chemistry/metabolism
MH  - Adenosine Triphosphate/chemistry/metabolism
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Conserved Sequence/genetics
MH  - Crystallization
MH  - Crystallography, X-Ray
MH  - Dimerization
MH  - Evolution, Molecular
MH  - Genes/genetics
MH  - Glutathione/chemistry/metabolism
MH  - Glutathione Synthase/*chemistry/deficiency/*genetics/metabolism
MH  - Humans
MH  - Magnesium/chemistry/metabolism
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - *Mutation
MH  - Phosphates/chemistry/metabolism
MH  - Protein Structure, Secondary
MH  - Sulfates/chemistry/metabolism
PMC - PMC1171401
EDAT- 1999/06/16 00:00
MHDA- 1999/06/16 00:01
CRDT- 1999/06/16 00:00
PHST- 1999/06/16 00:00 [pubmed]
PHST- 1999/06/16 00:01 [medline]
PHST- 1999/06/16 00:00 [entrez]
AID - 10.1093/emboj/18.12.3204 [doi]
PST - ppublish
SO  - EMBO J. 1999 Jun 15;18(12):3204-13. doi: 10.1093/emboj/18.12.3204.