PMID- 25697423
OWN - NLM
STAT- MEDLINE
DCOM- 20160322
LR  - 20211203
IS  - 1520-5126 (Electronic)
IS  - 0002-7863 (Print)
IS  - 0002-7863 (Linking)
VI  - 137
IP  - 9
DP  - 2015 Mar 11
TI  - C-Terminal glycine-gated radical initiation by GTP 3',8-cyclase in the molybdenum 
      cofactor biosynthesis.
PG  - 3352-9
LID - 10.1021/ja512997j [doi]
AB  - The molybdenum cofactor (Moco) is an essential redox cofactor found in all 
      kingdoms of life. Genetic mutations in the human Moco biosynthetic enzymes lead 
      to a fatal metabolic disorder, Moco deficiency (MoCD). Greater than 50% of all 
      human MoCD patients have mutations in MOCS1A, a radical S-adenosyl-l-methionine 
      (SAM) enzyme involved in the conversion of guanosine 5'-triphosphate (GTP) into 
      cyclic pyranopterin monophosphate. In MOCS1A, one of the frequently affected 
      locations is the GG motif constituted of two consecutive Gly at the C-terminus. 
      The GG motif is conserved among all MOCS1A homologues, but its role in catalysis 
      or the mechanism by which its mutation causes MoCD was unknown. Here, we report 
      the functional characterization of the GG motif using MoaA, a bacterial homologue 
      of MOCS1A, as a model. Our study elucidated that the GG motif is essential for 
      the activity of MoaA to produce 3',8-cH2GTP from GTP (GTP 3',8-cyclase), and that 
      synthetic peptides corresponding to the C-terminal region of wt-MoaA rescue the 
      GTP 3',8-cyclase activity of the GG-motif mutants. Further biochemical 
      characterization suggested that the C-terminal tail containing the GG motif 
      interacts with the SAM-binding pocket of MoaA, and is essential for the binding 
      of SAM and subsequent radical initiation. In sum, these observations suggest that 
      the C-terminal tail of MoaA provides an essential mechanism to trigger the free 
      radical reaction, impairment of which results in the complete loss of catalytic 
      function of the enzyme, and causes MoCD.
FAU - Hover, Bradley M
AU  - Hover BM
AD  - Department of Biochemistry, Duke University Medical Center , Durham, North 
      Carolina 27710, United States.
FAU - Yokoyama, Kenichi
AU  - Yokoyama K
LA  - eng
GR  - R01 GM112838/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150302
PL  - United States
TA  - J Am Chem Soc
JT  - Journal of the American Chemical Society
JID - 7503056
RN  - 0 (Coenzymes)
RN  - 0 (Metalloproteins)
RN  - 0 (Molybdenum Cofactors)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Pteridines)
RN  - 7YNJ3PO35Z (Hydrogen)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - ATN6EG42UQ (molybdenum cofactor)
RN  - EC 3.- (Hydrolases)
RN  - EC 3.3.1.2 (S-adenosylmethionine enzyme MoaA, Staphylococcus aureus)
RN  - EC 4.1.- (Carbon-Carbon Lyases)
RN  - EC 4.1.- (MOCS1 protein, human)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Amino Acid Motifs
MH  - Binding Sites
MH  - Carbon-Carbon Lyases
MH  - Coenzymes/*biosynthesis
MH  - Escherichia coli/genetics
MH  - Glycine/*metabolism
MH  - Guanosine Triphosphate/metabolism
MH  - Hydrogen/metabolism
MH  - Hydrolases/*chemistry/genetics/*metabolism
MH  - Kinetics
MH  - Metalloproteins/*biosynthesis
MH  - Molybdenum Cofactors
MH  - Mutation
MH  - Nuclear Proteins/chemistry/metabolism
MH  - Protein Conformation
MH  - Pteridines
PMC - PMC4831585
MID - NIHMS704684
COIS- Notes The authors declare no competing financial interest.
EDAT- 2015/02/24 06:00
MHDA- 2016/03/24 06:00
PMCR- 2016/04/14
CRDT- 2015/02/21 06:00
PHST- 2015/02/21 06:00 [entrez]
PHST- 2015/02/24 06:00 [pubmed]
PHST- 2016/03/24 06:00 [medline]
PHST- 2016/04/14 00:00 [pmc-release]
AID - 10.1021/ja512997j [doi]
PST - ppublish
SO  - J Am Chem Soc. 2015 Mar 11;137(9):3352-9. doi: 10.1021/ja512997j. Epub 2015 Mar 
      2.