Human Molecular Genetics, Vol 6, 2043-2050, Copyright © 1997 by Oxford University Press
G Brodsky, T Barnes, J Bleskan, L Becker, M Cox and D Patterson
Purines are critical for energy metabolism, cell signalling and cell
reproduction. Nevertheless, little is known about the regulation of this
essential biochemical pathway during mammalian development. In humans, the
second, third and fifth steps of de novo purine biosynthesis are catalyzed
by a trifunctional protein with glycinamide ribonucleotide synthetase
(GARS), aminoimidazole ribonucleotide synthetase (AIRS) and glycinamide
ribonucleotide formyltransferase (GART) enzymatic activities. The gene
encoding this trifunctional protein is located on chromosome 21. The enzyme
catalyzing the intervening fourth step of de novo purine biosynthesis,
phosphoribosylformylglycineamide amidotransferase (FGARAT), is encoded by a
separate gene on chromosome 17. To investigate the regulation of these
proteins, we have generated monoclonal and/or polyclonal antibodies
specific to each of these enzymatic domains. Using these antibodies on
western blots of Chinese hamster ovary (CHO) cells transfected with the
human GARS-AIRS-GART gene, we show that this gene encodes not only the
trifunctional protein of 110 kDa, but also a monofunctional GARS protein of
50 kDa. This carboxy-truncated human GARS protein is produced by
alternative splicing resulting in the use of a polyadenylation site in the
intron between the terminal GARS and the first AIRS exons. The expression
of both the GARS and GARS-AIRS- GART proteins are regulated during
development of the human cerebellum, while the expression of FGARAT appears
to be constitutive. All three proteins are expressed at high levels during
normal prenatal cerebellum development while the GARS and GARS-AIRS-GART
proteins become undetectable in this tissue shortly after birth. In
contrast, the GARS and GARS-AIRS-GART proteins continue to be expressed
during the postnatal development of the cerebellum in individuals with Down
syndrome.
ARTICLES
The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally overexpressed in cerebellum of individuals with Down syndrome
Eleanor Roosevelt Institute, 1899 Gaylord Street, Denver, CO 80206, USA. garyb@eri.uchsc.edu
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