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7x5n

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Crystal structure of E. faecium SHMT in complex with (+)-SHIN-1 and PLP-Ser

Structural highlights

7x5n is a 2 chain structure with sequence from Enterococcus faecium. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

I3U4H4_ENTFD Catalyzes the reversible interconversion of serine and glycine with tetrahydrofolate (THF) serving as the one-carbon carrier. This reaction serves as the major source of one-carbon groups required for the biosynthesis of purines, thymidylate, methionine, and other important biomolecules. Also exhibits THF-independent aldolase activity toward beta-hydroxyamino acids, producing glycine and aldehydes, via a retro-aldol mechanism.[HAMAP-Rule:MF_00051]

Publication Abstract from PubMed

Serine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH(2)-THF) from tetrahydrofolate with serine to glycine conversion. SHMT is a potential drug target in parasites, viruses and cancer. (+)-SHIN-1 was developed as a human SHMT inhibitor for cancer therapy. However, the potential of SHMT as an antibacterial target is unknown. Here, we show that (+)-SHIN-1 bacteriostatically inhibits the growth of Enterococcus faecium at a 50% effective concentration of 10(-11) M and synergistically enhances the antibacterial activities of several nucleoside analogues. Our results, including crystal structure analysis, indicate that (+)-SHIN-1 binds tightly to E. faecium SHMT (efmSHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efmSHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efmSHMT. The findings highlight the potency of SHMT as an antibacterial target and the possibility of developing SHMT inhibitors for treating bacterial, viral and parasitic infections and cancer.

Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors.,Makino Y, Oe C, Iwama K, Suzuki S, Nishiyama A, Hasegawa K, Okuda H, Hirata K, Ueno M, Kawaji K, Sasano M, Usui E, Hosaka T, Yabuki Y, Shirouzu M, Katsumi M, Murayama K, Hayashi H, Kodama EN Commun Biol. 2022 Jun 23;5(1):619. doi: 10.1038/s42003-022-03555-x. PMID:35739195^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Makino Y, Oe C, Iwama K, Suzuki S, Nishiyama A, Hasegawa K, Okuda H, Hirata K, Ueno M, Kawaji K, Sasano M, Usui E, Hosaka T, Yabuki Y, Shirouzu M, Katsumi M, Murayama K, Hayashi H, Kodama EN. Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors. Commun Biol. 2022 Jun 23;5(1):619. PMID:35739195 doi:10.1038/s42003-022-03555-x