9j4g

From Proteopedia

Crystal structure of SHMT from E. faecium with (+)-SHIN-2

Structural highlights

9j4g 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 1.95Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A0A133CK16_ENTFC 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

Novel classes of antibiotics are needed to improve the resilience of the healthcare system to antimicrobial resistance (AMR), including vancomycin resistance. vanA gene cluster is a cause of vancomycin resistance. This gene cluster is transferred and spreads vancomycin resistance from Enterococcus spp. to Staphylococcus aureus. Therefore, novel antibacterial agents are required to combat AMR, including vanA-type vancomycin resistance. Serine hydroxymethyltransferase (SHMT) is a key target of antibacterial agents. However, the specific binding mechanisms of SHMT inhibitors remain unclear. Detailed structural information will contribute to understanding these mechanisms. In this study, we found that (+)-SHIN-2, the first in vivo active inhibitor of human SHMT, is strongly bound to the Enterococcus faecium SHMT (efmSHMT). Comparison of the crystal structures of apo- and (+)-SHIN-2-boud efmSHMT revealed that (+)-SHIN-2 stabilized the active site loop of efmSHMT via hydrogen bonds, which are critical for efmSHMT inhibition. Additionally, (+)-SHIN-2 formed hydrogen bonds with serine, forming the Schiff's base with pyridoxal 5'-phosphate, which is a co-factor of SHMT. Furthermore, (+)-SHIN-2 exerted biostatic effects on vancomycin-susceptible and vanA-type vancomycin-resistant E. faecium in vitro, indicating that SHMT inhibitors do not induce cross-resistance to vanA-type vancomycin. Overall, these findings can aid in the design of novel SHMT inhibitors to combat AMR, including vancomycin resistance.

SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase.,Hayashi H, Saijo E, Hirata K, Murakami S, Okuda H, Kodama EN, Hasegawa K, Murayama K Arch Biochem Biophys. 2024 Sep 21;761:110160. doi: 10.1016/j.abb.2024.110160. PMID:39313141^[1]

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

References

↑ Hayashi H, Saijo E, Hirata K, Murakami S, Okuda H, Kodama EN, Hasegawa K, Murayama K. SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase. Arch Biochem Biophys. 2024 Sep 21;761:110160. PMID:39313141 doi:10.1016/j.abb.2024.110160