Editing Pyruvate kinase (section)

== Isozymes in vertebrates ==
Four [[isozyme]]s of pyruvate kinase expressed in vertebrates: L (liver), R (erythrocytes), M1 (muscle and brain) and M2 (early fetal tissue and most adult tissues). The L and R isozymes are expressed by the gene [[PKLR]], whereas the M1 and M2 isozymes are expressed by the gene [[PKM2]]. The R and L isozymes differ from M1 and M2 in that they are allosterically regulated. Kinetically, the R and L isozymes of pyruvate kinase have two distinct conformation states; one with a high substrate affinity and one with a low substrate affinity. The R-state, characterized by high substrate affinity, serves as the activated form of pyruvate kinase and is stabilized by PEP and [[fructose 1,6-bisphosphate]] (FBP), promoting the glycolytic pathway. The T-state, characterized by low substrate affinity, serves as the inactivated form of pyruvate kinase, bound and stabilized by ATP and [[alanine]], causing phosphorylation of pyruvate kinase and the inhibition of glycolysis.<ref name=":2">{{cite journal | vauthors = Muirhead H | title = Isoenzymes of pyruvate kinase | journal = Biochemical Society Transactions | volume = 18 | issue = 2 | pages = 193–6 | date = April 1990 | pmid = 2379684 | doi = 10.1042/bst0180193 | s2cid = 3262531 }}</ref> The M2 isozyme of pyruvate kinase can form tetramers or dimers. Tetramers have a high affinity for PEP, whereas, dimers have a low affinity for PEP. Enzymatic activity can be regulated by phosphorylating highly active tetramers of PKM2 into an inactive dimers.<ref>{{cite journal | vauthors = Eigenbrodt E, Reinacher M, Scheefers-Borchel U, Scheefers H, Friis R | title = Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells | journal = Critical Reviews in Oncogenesis | volume = 3 | issue = 1–2 | pages = 91–115 | date = 1992-01-01 | pmid = 1532331 }}</ref>

The PKM gene consists of 12 [[exon]]s and 11 [[intron]]s. PKM1 and PKM2 are different [[Alternative splicing|splicing]] products of the M-gene (PKM1 contains exon 9 while PKM2 contains exon 10) and solely differ in 23 amino acids within a 56-amino acid stretch (aa 378-434) at their [[C-terminal|carboxy terminus]].<ref>{{cite journal | vauthors = Noguchi T, Inoue H, Tanaka T | title = The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing | journal = The Journal of Biological Chemistry | volume = 261 | issue = 29 | pages = 13807–12 | date = October 1986 | doi = 10.1016/S0021-9258(18)67091-7 | pmid = 3020052 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dombrauckas JD, Santarsiero BD, Mesecar AD | title = Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis | journal = Biochemistry | volume = 44 | issue = 27 | pages = 9417–29 | date = July 2005 | pmid = 15996096 | doi = 10.1021/bi0474923 | s2cid = 24625677 }}</ref> The PKM gene is regulated through heterogenous ribonucleotide proteins like hnRNPA1 and hnRNPA2.<ref>{{cite journal | vauthors = Chen M, Zhang J, Manley JL | title = Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA | journal = Cancer Research | volume = 70 | issue = 22 | pages = 8977–80 | date = November 2010 | pmid = 20978194 | pmc = 2982937 | doi = 10.1158/0008-5472.CAN-10-2513 }}</ref> Human PKM2 monomer has 531 amino acids and is a single chain divided into A, B and C domains. The difference in amino acid sequence between PKM1 and PKM2 allows PKM2 to be allosterically regulated by FBP and for it to form dimers and tetramers while PKM1 can only form tetramers.<ref name=":02">{{cite journal | vauthors = Prakasam G, Iqbal MA, Bamezai RN, Mazurek S | title = Posttranslational Modifications of Pyruvate Kinase M2: Tweaks that Benefit Cancer | journal = Frontiers in Oncology | volume = 8 | pages = 22 | date = 2018 | pmid = 29468140 | pmc = 5808394 | doi = 10.3389/fonc.2018.00022 | doi-access = free }}</ref>