{PDOC00072}
{PS00075; DHFR_1}
{PS51330; DHFR_2}
{BEGIN}
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* Dihydrofolate reductase (DHFR) domain signature and profile *
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Dihydrofolate reductases (DHFRs) (EC 1.5.1.3) [1] are ubiquitous enzymes which
catalyze the   NADPH-linked   reduction   of   7,8-dihydrofolate  to  5,6,7,8-
tetrahydrofolate. DHFRs  are  also  capable  of  catalyzing  the  NADPH-linked
reduction of  folate  to 7,8-dihydrofolate, but at a lesser rate, which varies
among species.  They  can  be  inhibited  by  a  number of antagonists such as
trimethroprim and   methotrexate   which   are   used   as   antibacterial  or
anticancerous agents.

Thymidylate synthase  (TS)  (see  <PDOC00086>)  and  DHFR  catalyze sequential
reactions in  the  thymidylate  cycle, which supplies cells with their sole de
novo source  of  2'-deoxythymidylate  (dTMP) for DNA synthesis. TS catalyzes a
reductive methylation  of  2'deoxyuridylate  (dUMP)  to form dTMP in which the
cofactor for  the  reaction,  5,10-methylenetetrahydrofolate  is  converted to
dihydrofolate (FH(2)).  DHFR then reduces FH(2) to tetrahydrofolate (FH(4)) in
a reaction   requiring   NADPH.   In  sources  as  diverse  as  bacteriophage,
prokaryotes, fungi,  mammalian  viruses,  and  vertebrates,  TS  and  DHFR are
distinct monofunctional enzymes. Protozoa and at least some plants are unusual
in having  a  joined  bifunctional  polypetide  that  catalyzes both reactions
[2,3].

An eight-stranded  beta  sheet  consisting  of  seven  parallel  strands and a
carboxy-terminal antiparallel strand composes the core of the DHFR domain. The
beta-sheet core is flanked by alpha-helices (see <PDB:1DRH>) [2-6].

We have  derived  a  signature pattern from a region in the N-terminal part of
the DHFR  domain, which includes a conserved Pro-Trp dipeptide; the tryptophan
has been  shown  [7] to be involved in the binding of substrate by the enzyme.
We have also developed a profile, which covers the entire DHFR domain.

-Consensus pattern: [LVAGC]-[LIF]-G-x(4)-[LIVMF]-P-W-x(4,5)-[DE]-x(3)-[FYIV]-
                    x(3)-[STIQ]
-Sequences known to belong to this class detected by the pattern: ALL,  except
 for type II bacterial, plasmid-encoded, dihydrofolate reductases which do not
 belong to the same class of enzymes.
-Other sequence(s) detected in Swiss-Prot: 1.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: September 2007 / Text revised; profile added.

[ 1] Harpers' Review of Biochemistry, Lange, Los Altos (1985).
[ 2] Knighton D.R., Kan C.-C., Howland E., Janson C.A., Hostomska Z.,
     Welsh K.M., Matthews D.A.
     "Structure of and kinetic channelling in bifunctional dihydrofolate
     reductase-thymidylate synthase."
     Nat. Struct. Biol. 1:186-194(1994).
     PubMed=7656037
[ 3] Yuvaniyama J., Chitnumsub P., Kamchonwongpaisan S., Vanichtanankul J.,
     Sirawaraporn W., Taylor P., Walkinshaw M.D., Yuthavong Y.
     "Insights into antifolate resistance from malarial DHFR-TS
     structures."
     Nat. Struct. Biol. 10:357-365(2003).
     PubMed=12704428; DOI=10.1038/nsb921
[ 4] Davies J.F. II, Delcamp T.J., Prendergast N.J., Ashford V.A.,
     Freisheim J.H., Kraut J.
     "Crystal structures of recombinant human dihydrofolate reductase
     complexed with folate and 5-deazafolate."
     Biochemistry 29:9467-9479(1990).
     PubMed=2248959
[ 5] McTigue M.A., Davies J.F. II, Kaufman B.T., Kraut J.
     "Crystal structure of chicken liver dihydrofolate reductase complexed
     with NADP+ and biopterin."
     Biochemistry 31:7264-7273(1992).
     PubMed=1510919
[ 6] Reyes V.M., Sawaya M.R., Brown K.A., Kraut J.
     "Isomorphous crystal structures of Escherichia coli dihydrofolate
     reductase complexed with folate, 5-deazafolate, and
     5,10-dideazatetrahydrofolate: mechanistic implications."
     Biochemistry 34:2710-2723(1995).
     PubMed=7873554
[ 7] Bolin J.T., Filman D.J., Matthews D.A., Hamlin R.C., Kraut J.
     "Dihydrofolate reductase. The stereochemistry of inhibitor
     selectivity."
     J. Biol. Chem. 257:13650-13662(1982).
     PubMed=3880743;

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