Mimosine targets serine hydroxymethyltransferase

Area of Science:

• Molecular Biology
• Biochemistry
• Cell Biology

Background:

• Mimosine, a plant amino acid, is a potent inhibitor of DNA replication in mammalian cells.
• Previous studies showed mimosine photocross-links to a 50-kDa polypeptide (p50) in Chinese hamster ovary (CHO) cells.

Purpose of the Study:

• To identify the 50-kDa polypeptide (p50) that mimosine binds to.
• To investigate the role of this protein in mimosine's DNA replication inhibition.
• To explore the potential of targeting this protein for cancer therapy.

Main Methods:

• Tandem mass spectrometry was used to sequence tryptic peptides from the mimosine-cross-linked p50.
• Antibody precipitation was employed to verify the protein's identity.
• Mimosine sensitivity was assessed in mimosine-resistant and glycinamide-auxotrophic (gly-) CHO cell lines.

Main Results:

• Sequencing revealed p50 is highly similar to rabbit mitochondrial serine hydroxymethyltransferase (mSHMT).
• An antibody to mSHMT precipitated the mimosine-p50 complex, confirming the identity.
• Mimosine's cross-linking to p50 was significantly reduced in mimosine-resistant cells.
• The gly- cell line, lacking mitochondrial SHMT, remained sensitive to mimosine, suggesting inhibition of both mitochondrial and cytosolic forms.

Conclusions:

• Mimosine inhibits DNA replication by targeting serine hydroxymethyltransferase (SHMT).
• SHMT is involved in thymidylate biosynthesis, making it a potential target for anti-cancer drug development.
• Mimosine may inhibit both mitochondrial and cytosolic forms of SHMT.