A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight

Abstract

Metabolic reprogramming is a key hallmark of cancer and shifts cellular metabolism to meet the demands of biomass production necessary for abnormal cell reproduction. One-carbon metabolism (1CM) contributes to many biosynthetic pathways that fuel growth and is comprised of a complex network of enzymes. Methotrexate and 5-fluorouracil were pioneering drugs in this field and are still widely used today as anticancer agents as well as for other diseases such as arthritis. Besides dihydrofolate reductase and thymidylate synthase, two other enzymes of the folate cycle arm of 1CM have not been targeted clinically: serine hydroxymethyltransferase (SHMT) and methylenetetrahydrofolate dehydrogenase (MTHFD). An increasing body of literature suggests that the mitochondrial isoforms of these enzymes (SHMT2 and MTHFD2) are clinically relevant in the context of cancer. In this review, we focused on the 1CM pathway as a target for cancer therapy and, in particular, SHMT2 and MTHFD2. The function, regulation, and clinical relevance of SHMT2 and MTHFD2 are all discussed. We expand on previous clinical studies and evaluate the prognostic significance of these critical enzymes by performing a pan-cancer analysis of patient data from the The Cancer Genome Atlas and a transcriptional coexpression network enrichment analysis. We also provide an overview of preclinical and clinical inhibitors targeting the folate pathway, the methionine cycle, and folate-dependent purine biosynthesis enzymes.

Metformin Is a Pyridoxal-5′-phosphate (PLP)-Competitive Inhibitor of SHMT2

“…Cytosolic SGOC enzymes such as dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have been important targets for pioneering anti-folates such as aminopterin, methotrexate, pemetrexed and 5-fluorouracil [61,62]. Although there has been an ever-increasing focus on exploiting the essential role of mitochondrial SGOC enzymes as critical sources of 1C units to sustain the malignant phenotype in tumors, small-molecule inhibitors of the first (SHMT2) and second (5,10-methylene tetrahydrofolate dehydrogenase 2 (MTHFD2)) mitochondrial SGOC enzymes have not yet reached the clinic [2,[63][64][65]. Whereas the search for selective serine analogues and amino acid derivatives as SHMT2 inhibitors has not been very successful, the pyrazolopyrans scaffold represents the leading series of compounds accounting for the SHMT1/2 inhibitor space.…”

“…Thus, rather than aggravating the existing mCI deficiency in mice lacking the mCI subunit NDUFS3, metformin phenocopied the pharmacological inhibitor of SHMT1/2 SHIN2 to attenuate the so-called clasping phenotype [70,71]. Further studies are warranted to better understand the molecular mechanisms underlying the phenotypic outcomes arising from single and combined treatments with weak (millimolar) regulators of SHMT2 activity impeding a dimer-totetramer transition of SHMT2 in a PLP-dependent manner (e.g., the biguanide metformin) and potent (nanomolar) SHMT2 inhibitors directly occupying the folate binding site of SHMT2 such as SHIN-like optimized pyrazolopyrans or sertraline [4,[63][64][65][66]. Intriguingly, the SHMT1/2 inhibitor SHIN1 has been found to notably augment cancer cell proliferation in the presence of the mCI inhibitors metformin, phenformin, and rotenone [71].…”

Myasthenia gravis: The pharmacological basis of traditional Chinese medicine for its clinical application

“…In addition, the occurrence of MG is related to thymic abnormality, viral infection, and genetic factors. In parallel, recently, various pharmacology networks designed on numerous diseases such as cancer by authors 47–51 . Therefore, the above targets and signaling pathways provide new ideas and goals for future MG research.…”

Lysine Fatty Acylation: Regulatory Enzymes, Research Tools, and Biological Function

“…SHMT2 catalyzes the reversible conversion of serine and THF to glycine and methylene-THF in the mitochondria. High levels of SHMT2 are associated with poor patient prognosis in several cancers and inhibitors that target both SHMT2 and SHMT1 (which catalyzes the same reaction in the cytoplasm) have shown promising results in initial cellular and mouse studies (Cuthbertson et al, 2021). Additionally, SHMT2 was found to regulate immune signaling as a component of the BRISC deubiquitylase complex.…”