Can glycine be transformed into threonine at nonketonic hyperglycinemia?

In the forties of the XX century, it was stated by Rose what amino acids are essential that is they are not synthesized in the organism of man and animals if they cannot be found in food. Though threonine is considered an essential amino acid, nevertheless as far back as the eighties of the last century many papers and theses which described ways of mutual transformation of threonine and glycine, catalyzed by threonine aldolase, were published, which by definition contradicts the essentiality of threonine. In particular, an increase in threonine content in the tissues of human beings who were diagnosed with nonketotic hyperglycinemia was explained by its synthesis from glycine under the influence of threoninealdolase. Some authors even ascribed to serine hydroxymethyltransferase, an enzyme which catalyzes mutual transformation of two non-essential amino acids, serine and glycine, the identity to threonine aldolase. That was the reason why the view that threonine disintegrates under the action of serine hydroxymethyltransferase appeared. Later it was determined that threoninealdolase which is very active in bacteria is not present in animals’ tissues and that serine hydroxymethyltransferase does not affect threonine in mammals; thus in mammals the aldol cleavage of threonine is impossible, to say nothing about its reversibility. After that it seems there must not be any doubt that the synthesis of threonine in animals is impossible as both enzymes which catalyze disintegration of threonine (threonine dehydratase and threonine dehydrogenase) split threonine irreversibly; the fact has been known since the discovery of the enzymes. However, recently some papers in which transformation of glycine into threonine in human beings and mammals is ascribed to threonine dehydrogenase have appeared. It should be noted that threonine dehydrogenase in humans is absent. In the present paper impossibility of transformation of glycine into threonine in human beings and mammals is stated on the biochemical level which agrees with the fact that threonine is an essential amino acid.

1. Meister A. Biochemistry of amino acids. Moscow: Inostrannaya literatura, 1961.530 р. [In Russian].

2. Schirch I., Gross T. Serine transhydroxymethylase Identification as the threonine and allothreonine aldolases. J. Biol. Chem. 1968;243(21):5651–5651.

3. Krieger I., Nigro M. Evidence for defective threonine metabolism in nonketotic hyperglycinaemia. J. Inher. Metab. Dis. 1983;6(1):40–43. doi: 10.1007/BF02391192

4. Krieger I., Booth F. Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia. J. Inher. Metab. Dis. 1984;7(2):53–56. doi: 10.1007/BF01805800

5. Yeung Y.G. Threonine aldolase is not a genuine enzyme in rat liver. Biochem J. 1986;237(1):187–190. doi: 10.1042/bj2370187

6. Pagani R., Leoncini R., Terzuoli L., Chen J., Pizzichini M., Marinello E. DL-allothreonine and Lthreonine aldolase in rat liver. Biochem. Soc. Trans. 1991;19(3):346S.

7. Ogawa H., Gomi T., Fujioka M. Serine hydroxymethyltransferase and threonine aldolase are they identical? Int. J. Biochem. Cell. Biol. 2000;32(3):289–301. doi: 10.1016/s1357-2725(99)00113-2

8. Swanson M.A., Miller K., Young S.P., Tong S., Ghaloul-Gonzalez L., Neira-Fresneda J., Schlichting L., Peck C., Gabel L., Friederich M., van Hove J.L.K. Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia. J. Inherit Metab. Dis. 2022;45(4):734–747. doi: 10.1002/jimd.12500

9. Edgar A.J. The human L-threonine-3-dehydrogenase gene is an expressed pseudogene. BMC Biochem.2002;3:18. doi: 10.1186/1471-2156-3-18

10. Kim D., Fiske B.P., Birsoy K., Freinkman E., Kami K., Possemato R.L., Chudnovsky Y., Pacold M.E., Chen W.W., Cantor J.R., … Sabatini D.M. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature. 2015;520(7547):363–367. doi: 10.1038/nature14363

11. Pokrovskii A.A. The role of biochemistry in the development of nutritional science. Moscow: Nauka, 1974. 127 р. [In Russian].

12. Watanabe R., Fujimura S., Kadowaki M., Ishibashi T. Effects of dietary threonine levels on the threonine-degrading enzyme activities and tissue threonine related amino acid concentration in rats. Anim. Sci. Technol. 1998;(69):108–116.

13. Housse J.D., Hall B.N., Brosnan J.T. Threonine metabolism in isolated rat hepatocytes. Am. J. Physiol. Endocrinol. Metab. 2001;281(6):Е1300–1307. doi: 10.1152/ajpendo.2001.281.6.E1300

14. Nagao K., Bannai M., Seki S., Mori M., Takahashi M. Adaptational modification of serine and threonine metabolism in the liver to essential amino acid deficiency in rats. Amino Acids. 2009;36(3):555–362. doi: 10.1007/s00726-008-0117-7

15. Neuberger A. Glycine formation from L-threonine. Comp. Biochem. 1981;(19A):257–303. doi: 10.1042/bst0071276

16. Bird M.I., Nunn P.B. Measurement of L-threonine aldolase activity in rat liver. Biochem. Soc. Trans. 1979;7(6):1274–1276. doi: 10.1042/bst0071274

17. Green M.L., Elliott W.H., The enzymic formation of aminoacetone from threonine and its further metabolism. Biochem. J. 1964;92(3):537–549. doi: 10.1042/bj0920537

18. Chuanchin H., Hao G., Jiaxu W., Weiguang L., Yide M., Mian W. Regulation of L-threonine dehydrogenase in somatic cell reprogramming. Stem Cells.2013;31(5):953–965. doi: 10.1002/stem.1335

19. Winkle L.J.V., Gallet V., Iannaccone P.M. Threonine appears to be essential for proliferation of human as well as mouse embryonic stem cells. Front. Cell. Dev. Biol. 2014:2:18. doi: 10.3389/fcell.2014.00018

20. Fubara B., Eckenrode F., Tresse T., Davis L.Purification and propertis of aminoacetone synthetase from beef liver mitochondria. J. Biol. Chem. 1986;261( 26):12189–12196.

21. Bender D.A. Amino acid metabolism. L., 2012. 480 p.

22. Malinovsky A.V. Reason for indispensability of threonine in humans and other mammals in comparative aspect. Biochemistry (Mosc.). 2017;82(9):1055– 1060. doi: 10.1134/S0006297917090097