{PDOC60001}
{PS60001; NOS}
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* Nitric oxide synthase (NOS) signature *
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Nitric oxide  synthase (EC 1.14.13.39) (NOS) enzymes produce nitric oxide (NO)
by  catalyzing a five-electron oxidation of a guanidino nitrogen of L-arginine
(L-Arg).  Oxidation  of  L-Arg  to  L-citrulline  occurs  via  two  successive
monooxygenation   reactions   producing   N(omega)-hydroxy-L-arginine   as  an
intermediate.  2  mol of O(2) and 1.5 mol of NADPH are consumed per mole of NO
formed [1].

Arginine-derived  NO  synthesis  has  been identified in mammals, fish, birds,
invertebrates, plants, and bacteria [1]. Best studied are mammals, where three
distinct  genes  encode  NOS  isozymes:  neuronal  (nNOS  or NOS-1), cytokine-
inducible  (iNOS  or NOS-2) and endothelial (eNOS or NOS-3) [2]. iNOS and nNOS
are  soluble  and  found  predominantly in the cytosol, while eNOS is membrane
associated.  The  enzymes  exist as homodimers, each monomer consisting of two
major  domains:  an N-terminal oxygenase domain, which belongs to the class of
heme-thiolate proteins, and a C-terminal reductase domain, which is homologous
to  NADPH:P450  reductase  (EC  1.6.2.4).  The  interdomain linker between the
oxygenase  and reductase domains contains a calmodulin (CaM)-binding sequence.
NOSs are   the  only  enzymes  known  to  simultaneously  require  five  bound
cofactors/prosthetic groups: FAD, FMN, heme, tetrahydrobiopterin and Ca2+-CaM.
The animal  NOS  isozymes are catalytically self-sufficient. The electron flow
in the NO synthase reaction is: NADPH --> FAD --> FMN --> heme --> O(2).

eNOS  localisation  to  endothelial  membranes  is mediated by cotranslational
N-terminal myristoylation    (see    <PDOC00008>)    and    post-translational
palmitoylation [3]. The subcellular localisation of nNOS in skeletal muscle is
mediated by  anchoring  of  nNOS to dystrophin. nNOS contains an additional N-
terminal domain, the PDZ domain (see <PDOC50106>) [4].

Some  bacteria,  like  Bacillus  halodurans,  Bacillus subtilis or Deinococcus
radiodurans, contain homologs of NOS oxygenase domain.

The pattern is directed against the N-terminal heme binding site.

-Consensus pattern: [GR]-C-[IV]-G-R-[ILS]-x-W
                    [C is the heme iron ligand]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Expert(s) to contact by email:
           Degtyarenko K.N.; kirill@ebi.ac.uk

-Last update: December 2001 / First entry.

[ 1] Liu Q., Gross S.S.
     "Binding sites of nitric oxide synthases."
     Methods Enzymol. 268:311-324(1996).
     PubMed=8782597
[ 2] Knowles R.G., Moncada S.
     "Nitric oxide synthases in mammals."
     Biochem. J. 298:249-258(1994).
     PubMed=7510950
[ 3] Liu J., Hughes T.E., Sessa W.C.
     "The first 35 amino acids and fatty acylation sites determine the
     molecular targeting of endothelial nitric oxide synthase into the
     Golgi region of cells: a green fluorescent protein study."
     J. Cell Biol. 137:1525-1535(1997).
     PubMed=9199168
[ 4] Ponting C.P., Phillips C.
     "DHR domains in syntrophins, neuronal NO synthases and other
     intracellular proteins."
     Trends Biochem. Sci. 20:102-103(1995).
     PubMed=7535955

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