Serine hydroxymethyltransferase (SHMT) is a pivotal enzyme in one-carbon metabolism that catalyses the reversible conversion of serine and tetrahydrofolate into glycine and methylenetetrahydrofolate. It exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms. Research on one-carbon metabolism in cancer cell lines has shown that SHMT1 preferentially catalyses serine synthesis, whereas in mitochondria SHMT2 is involved in serine breakdown. Recent research has focused on the identification of inhibitors that bind at the folate pocket. We have previously found that a representative derivative of the pyrazolopyran scaffold, namely 2.12, inhibits both SHMT isoforms, with a preference for SHMT1, causing apoptosis in lung cancer cell lines. Here we show that the affinity of 2.12 for SHMT depends on the identity of the amino acid substrate bound to the enzyme. The dissociation constant of 2.12 is 50-fold lower when it binds to SHMT1 enzyme-serine complex, as compared to the enzyme-glycine complex. Evidence is presented for a similar behaviour of compound 2.12 in the cellular environment. These findings suggest that the presence and identity of the amino acid substrate should be considered when designing SHMT inhibitors. Moreover, our data provide the proof-of-concept that SHMT inhibitors selectively targeting the directionality of one-carbon metabolism flux could be designed.

Differential inhibitory effect of a pyrazolopyran compound on human serine hydroxymethyltransferase-amino acid complexes / Tramonti, Angela; Paiardini, Alessandro; Paone, Alessio; Bouzidi, Amani; Giardina, Giorgio; Guiducci, Giulia; Magnifico, Maria Chiara; Rinaldo, Serena; Mcdermott, Lee; Menendez, Javier A.; Contestabile, Roberto; Cutruzzolà, Francesca. - In: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. - ISSN 0003-9861. - STAMPA. - 653:(2018), pp. 71-79. [10.1016/j.abb.2018.07.001]

Differential inhibitory effect of a pyrazolopyran compound on human serine hydroxymethyltransferase-amino acid complexes

Tramonti, Angela;Paiardini, Alessandro;Paone, Alessio;Bouzidi, Amani;Giardina, Giorgio;Guiducci, Giulia;Magnifico, Maria Chiara;Rinaldo, Serena;Contestabile, Roberto
;
Cutruzzolà, Francesca
2018

Abstract

Serine hydroxymethyltransferase (SHMT) is a pivotal enzyme in one-carbon metabolism that catalyses the reversible conversion of serine and tetrahydrofolate into glycine and methylenetetrahydrofolate. It exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms. Research on one-carbon metabolism in cancer cell lines has shown that SHMT1 preferentially catalyses serine synthesis, whereas in mitochondria SHMT2 is involved in serine breakdown. Recent research has focused on the identification of inhibitors that bind at the folate pocket. We have previously found that a representative derivative of the pyrazolopyran scaffold, namely 2.12, inhibits both SHMT isoforms, with a preference for SHMT1, causing apoptosis in lung cancer cell lines. Here we show that the affinity of 2.12 for SHMT depends on the identity of the amino acid substrate bound to the enzyme. The dissociation constant of 2.12 is 50-fold lower when it binds to SHMT1 enzyme-serine complex, as compared to the enzyme-glycine complex. Evidence is presented for a similar behaviour of compound 2.12 in the cellular environment. These findings suggest that the presence and identity of the amino acid substrate should be considered when designing SHMT inhibitors. Moreover, our data provide the proof-of-concept that SHMT inhibitors selectively targeting the directionality of one-carbon metabolism flux could be designed.
cancer metabolism; enzyme inhibition; isozymes; one carbon metabolism; pyrazolopyran scaffold; serine hydroxymethyltransferase; biophysics; biochemistry; molecular biology
01 Pubblicazione su rivista::01a Articolo in rivista
Differential inhibitory effect of a pyrazolopyran compound on human serine hydroxymethyltransferase-amino acid complexes / Tramonti, Angela; Paiardini, Alessandro; Paone, Alessio; Bouzidi, Amani; Giardina, Giorgio; Guiducci, Giulia; Magnifico, Maria Chiara; Rinaldo, Serena; Mcdermott, Lee; Menendez, Javier A.; Contestabile, Roberto; Cutruzzolà, Francesca. - In: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. - ISSN 0003-9861. - STAMPA. - 653:(2018), pp. 71-79. [10.1016/j.abb.2018.07.001]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1131469
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