Serine in plants: biosynthesis, metabolism, and functions Roc Ros 1 , Jesu ´s Mun ˜ oz-Bertomeu 1* , and Stephan Krueger 2 1 ERI de Biotecnologia i Biomedicina, Departament de Biologia Vegetal, Facultat de Farma ` cia, Universitat de Vale ` ncia, 46100 Burjassot (Valencia), Spain 2 Botanical Institute II, Cologne Biocenter, University of Cologne, D-50674 Cologne, Germany Serine (Ser) has a fundamental role in metabolism and signaling in living organisms. In plants, the existence of different pathways of Ser biosynthesis has complicated our understanding of this amino acid homeostasis. The photorespiratory glycolate pathway has been consid- ered to be of major importance, whereas the nonpho- torespiratory phosphorylated pathway has been relatively neglected. Recent advances indicate that the phosphorylated pathway has an important function in plant metabolism and development. Plants deficient in this pathway display developmental defects in embryos, male gametophytes, and roots. We propose that the phosphorylated pathway is more important than was initially thought because it is the only Ser source for specific cell types involved in developmental events. Here, we discuss its importance as a link between me- tabolism and development in plants. Serine functions in animals and plants In addition to forming part of proteins and performing catalytic functions in many enzymes, L-Ser participates in the biosynthesis of several biomolecules required for cell proliferation, including amino acids, nitrogenous bases, phospholipids, and sphingolipids (Figure 1). L-Ser also has an indispensable role in several cellular processes, such as the metabolism of one-carbon (C1) units [1], or in signaling mechanisms, where it is one of the three amino acids that are phosphorylated by kinases. Recent major advances in our understanding of specific Ser functions have been achieved in mammals. L-Ser is essential for normal embryonic development, especially for brain morphogenesis [2,3]. It also has a pivotal role in controlling cell proliferation, having been implicated in cancer progression [2,4–9]. L-Ser is an allosteric activator of enzymes like pyruvate kinase M2, which is overex- pressed in cancer cells [5]. It also induces metabolic remo- deling in cancer cells dependent on the tumor suppressor protein p53, which led researchers to suggest the potential role of L-Ser depletion in the treatment of p53-deficient tumors [7]. In plants, deficiencies in molecules derived from L-Ser have drastic consequences. For instance, deficiency in phos- phatidylserine, a relatively minor plant cell lipid, leads to alterations in microspore development and to a high embryo abortion rate in Arabidopsis (Arabidopsis thaliana) [10]. Mutants lacking Ser palmitoyltransferase, the enzyme par- ticipating in the first committed sphingolipid biosynthesis step by condensation of L-Ser with palmitoyl-CoA, display embryo and male gametophyte lethality [11,12]. Adult plants with reduced sphingolipid content present altered mineral ion homeostasis and are unable to survive [12,13]. L-Ser is also crucial for the regulation of methyl group transfer by providing tetrahydrofolate metabolism with C1 units [14,15]. Folate metabolism has proven essential for embryogenesis, post-embryonic root development, and photorespiration [16,17]. Finally, some evidence suggests that L-Ser is involved in the plant response to biotic and abiotic stresses [18–20]. In mammals and plants, additional non-metabolic func- tions for Ser have been postulated. L-Ser is the precursor of D-Ser, a well-known neuromodulator [2,21]. In plants, D- Ser has been assigned a signaling role between the male gametophyte and pistil communication, similar to that observed in animal nervous systems [22]. Arabidopsis knockout mutants for Ser racemase, the enzyme that converts L-Ser into D-Ser, display decreased glutamate receptor-like activity in pistils, affecting Ca 2+ influx across the plasma membrane and, in turn, pollen tube growth and morphogenesis [22]. In most organisms, L-Ser is primarily synthesized by the so-called ‘phosphorylated pathway’. In plants, L-Ser biosynthesis proceeds by different pathways (Figure 1), one that is associated with photorespiration, the glycolate pathway [23–27] and two nonphotorespiratory pathways, the phosphorylated and the glycerate pathways [28]. Given its fundamental role in plant metabolism and develop- ment, Ser homeostasis is expected to be strictly regulated. However, the coexistence of several L-Ser biosynthetic pathways complicates the understanding of the regulation of this essential process. L-Ser production through the glycolate pathway has been considered the most important [24,26]. No relevant information about the biological sig- nificance of the nonphotorespiratory pathways was avail- able until recently [18,29,30], probably because they were considered of minor importance. In this review, we focus on recent findings on the biological function of the phosphor- ylated pathway of L-Ser biosynthesis (PPSB). Opinion 1360-1385/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tplants.2014.06.003 Corresponding author: Ros, R. (roc.ros@uv.es). Keywords: serine biosynthesis; plants; phosphorylated serine biosynthesis pathway. * Current address: Instituto de Biologı ´a Molecular y Celular de Plantas (IBMCP), UPV- CSIC, 46022 Valencia, Spain 564 Trends in Plant Science, September 2014, Vol. 19, No. 9