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Parathyroid hormone (PTH), an 84-amino acid peptide, is the
major regulator of blood calcium homeostasis. Its mRNA, in addition to
encoding the mature peptide, also encodes a ``pre'' sequence
of 25 amino acids and a basic ``pro'' hexapeptide. To assess
which of the subtilisin-like prohormone convertases can process proPTH
to PTH we coinfected cells with a vaccinia virus construct expressing
human preproPTH and vaccinia virus constructs expressing furin, PC1 or
PC2. BSC-40 cells, having a constitutive secretory pathway, and GH4C1
cells, having a regulated secretory pathway, were used. PTH
biosynthetic products in cell extracts and media were purified by high
performance liquid chromatography, identified by radioimmunoassay, and
unambiguously defined as either proPTH or PTH by ion-spray mass
spectrometry. In both cell types, furin was the most effective in
processing proPTH to PTH. In all cases only PTH was released into the
medium. In addition, partially purified furin and PC1 were tested for
their ability to appropriately cleave a tridecapeptide spanning the
prohormone cleavage site found in proPTH. Here too furin was much more
effective at cleaving at the correct site. Northern blot analysis and
in situ hybridization showed that furin and preproPTH mRNA are
co-expressed in the parathyroid, whereas PC1, PC2, and PC5 are not and
PACE4 is expressed only at very low levels. Taken together these
studies strongly suggest that furin is the enzyme responsible for the
physiological processing of proPTH to PTH.
Volume 270,
Number 16,
Issue of April 21, pp. 9517-9525, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
A MASS SPECTROMETRIC STUDY
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