AB - Serine and glycine are biosynthetically linked, and together provide the essential precursors for the synthesis of proteins, nucleic acids, and lipids that are crucial to cancer cell growth. Moreover, serine/glycine biosynthesis also affects cellular antioxidative capacity, thus supporting tumour homeostasis. A crucial contribution of serine/glycine to cellular metabolism is through the glycine cleavage system, which refuels one-carbon metabolism; a complex cyclic metabolic network based on chemical reactions of folate compounds. The importance of serine/glycine metabolism is further highlighted by genetic and functional evidence indicating that hyperactivation of the serine/glycine biosynthetic pathway drives oncogenesis. Recent developments in our understanding of these pathways provide novel translational opportunities for drug development, dietary intervention, and biomarker identification of human cancers.
has 3 isozymes of aspartokinase that respond differently toeach of the 3 amino acids, with regard to enzyme inhibition and feedbackinhibition. The biosynthesis of lysine, methionine and threonine are not, then,controlled as a group.
Ignoring tyrosine (as it's immediate precursor is phenylalanine, an essentialamino acid), all of the nonessential amino acids (and we will include argininehere) are synthesized from intermediates of major metabolicpathways. Furthermore, the carbon skeletons of these amino acids are traceableto their corresponding ketoacids. Therefore, it could be possible tosynthesize any one of the nonessential amino acids directly by transaminatingits corresponding -ketoacid, if that ketoacid exists as a commonintermediate.
Asparagine and glutamine are the products of amidations of aspartate andglutamate, respectively. Thus, asparagine and glutamine, and the remainingnonessential amino acids are not directly the result of transamination of -ketoacidsbecause these are not common intermediates of the other pathways. Still, we willbe able to trace the carbon skeletons of all of these back to an -ketoacid.I make this point not because of any profound implications inherent in it, butrather as a way to simplify the learning of synthetic pathways of thenonessential amino acids.
So, the synthesis of asparagine is intrinsically tied to that of glutamine,and it turns out that glutamine is the amino group donor in the formation ofnumerous biosynthetic products, as well as being a storage form of NH3. Therefore, one would expect that glutamine synthetase, the enzyme responsiblefor the amidation of glutamate, plays a central role in the regulation ofnitrogen metabolism. We will now look into this control in more detail, beforeproceeding to the biosynthesis of the remaining nonessential amino acids.
Serine is important in in that it participates in the of and . It is the precursor to several amino acids including and , and in bacteria. It is also the precursor to numerous other metabolites, including and , which is the principal donor of one-carbon fragments in biosynthesis.
Glycine biosynthesis: (SHMT = serine transhydroxymethylase) also catalyzes the reversible conversions of -serine to (retro-aldol cleavage) and to (mTHF) (hydrolysis). SHMT is a (PLP) dependent enzyme. Glycine can also be formed from CO2, NH4+, and mTHF in a reaction catalyzed by .
Serine (abbreviated as Ser or S) encoded by the UCU, UCC, UCA, UCG, AGU and AGC is an ɑ-amino acid that is used in the biosynthesis of proteins. It contains an α- (which is in the − form under biological conditions), a (which is in the – form in physiological conditions), and a side chain consisting of a hydroxymethyl group (see ), classifying it as a amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid.
We will look at this pathway in a bit more detail, because it involves themolecule 5-phosphoribosyl--pyrophosphate (which wewill refer to as "PRPP" from now on). PRPP is also involved in thesynthesis of purines and pyrimidines, as we will soon see. In the first step ofhistidine synthesis, PRPP condenses with ATP to form a purine, N1-5'-phosphoribosylATP, in a reaction that is driven by the subsequent hydrolysis of thepyrophosphate that condenses out. Glutamine again plays a role as an amino groupdonor, this time resulting in the formation of 5-aminoamidazole-4-carboximideribonucleotide (ACAIR), which is an intermediate in purine biosynthesis.
The branch that leads towards tyrosine and phenylalanine has another branchpoint at prephenate. The only difference between the 2 resulting amino acids isthat the para carbon of the benzene ring of tyrosine is hydroxylated. Indeed, inmammals, phenylalanine is directly hydroxylated to tyrosine, catalyzed by theenzyme phenylalanine hydroxylase.
AB - Activation of serine biosynthesis supports growth and proliferation of cancer cells. Human cancers often exhibit overexpression of phosphoglycerate dehydrogenase (PHGDH), the metabolic enzyme that catalyses the reaction that diverts serine biosynthesis from the glycolytic pathway. By refueling serine biosynthetic pathways, cancer cells sustain their metabolic requirements, promoting macromolecule synthesis, anaplerotic flux and ATP. Serine biosynthesis intersects glutaminolysis and together with this pathway provides substrates for production of antioxidant GSH. In human lung adenocarcinomas we identified a correlation between serine biosynthetic pathway and p73 expression. Metabolic profiling of human cancer cell line revealed that TAp73 activates serine biosynthesis, resulting in increased intracellular levels of serine and glycine, associated to accumulation of glutamate, tricarboxylic acid (TCA) anaplerotic intermediates and GSH. However, at molecular level p73 does not directly regulate serine metabolic enzymes, but transcriptionally controls a key enzyme of glutaminolysis, glutaminase-2 (GLS-2). p73, through GLS-2, favors conversion of glutamine in glutamate, which in turn drives the serine biosynthetic pathway. Serine and glutamate can be then employed for GSH synthesis, thus the p73-dependent metabolic switch enables potential response against oxidative stress. In knockdown experiment, indeed, TAp73 depletion completely abrogates cancer cell proliferation capacity in serine/glycine-deprivation, supporting the role of p73 to help cancer cells under metabolic stress. These findings implicate p73 in regulation of cancer metabolism and suggest that TAp73 influences glutamine and serine metabolism, affecting GSH synthesis and determining cancer pathogenesis.
-Serine, synthesized in the brain by from -serine (its ), serves as a neuromodulator by coactivating , making them able to open if they then also bind . -serine is a potent at the site of the (NMDAR). For the receptor to open, glutamate and either glycine or -serine must bind to it. In fact, -serine is a more potent agonist at the glycine site on the NMDAR than glycine itself.