In enzymology, a diphthine synthase (EC 2.1.1.98) is an enzyme that catalyzes the chemical reaction

S-adenosyl-L-methionine + 2-(3-carboxy-3-aminopropyl)-L-histidine ${\displaystyle \rightleftharpoons }$ S-adenosyl-L-homocysteine + 2-[3-carboxy-3-(methylammonio)propyl]-L-histidine

Thus, the two substrates of this enzyme are S-adenosyl methionine and 2-(3-carboxy-3-aminopropyl)-L-histidine, whereas its two products are S-adenosylhomocysteine and [[2-[3-carboxy-3-(methylammonio)propyl]-L-histidine]].

This enzyme belongs to the family of transferases, specifically those transferring one-carbon group methyltransferases. The systematic name of this enzyme class is S-adenosyl-L-methionine:2-(3-carboxy-3-aminopropyl)-L-histidine methyltransferase. Other names in common use include S-adenosyl-L-methionine:elongation factor 2 methyltransferase, and diphthine methyltransferase.

As of late 2007, 84 structures have been solved for this class of enzymes, with PDB accession codes 1VCE, 1VHV, 1WDE, 1WNG, 2DEK, 2DSG, 2DSH, 2DSI, 2DV3, 2DV4, 2DV5, 2DV7, 2DXV, 2DXW, 2DXX, 2E07, 2E08, 2E15, 2E16, 2E17, 2E4N, 2E4R, 2E7R, 2E8H, 2E8Q, 2E8R, 2E8S, 2ED3, 2ED5, 2EEQ, 2EGB, 2EGL, 2EGS, 2EH2, 2EH4, 2EH5, 2EHC, 2EHL, 2EJJ, 2EJK, 2EJZ, 2EK2, 2EK3, 2EK4, 2EK7, 2EKA, 2EL0, 2EL1, 2EL2, 2EL3, 2ELD, 2ELE, 2EMR, 2EMU, 2EN5, 2ENI, 2HR8, 2HUQ, 2HUT, 2HUV, 2HUX, 2OWF, 2OWG, 2OWK, 2OWU, 2OWV, 2P2X, 2P5C, 2P5F, 2P6D, 2P6I, 2P6K, 2P6L, 2P9D, 2PB4, 2PB5, 2PB6, 2PCA, 2PCG, 2PCH, 2PCI, 2PCK, 2PCM, and 2Z6R.