Editing Pyruvate kinase (section)

=== Gene Regulation ===
[[Heterogeneous ribonucleoprotein particle|Heterogenous ribonucleotide proteins]] (hnRNPs) can act on the PKM gene to regulate expression of M1 and M2 isoforms. PKM1 and PKM2 isoforms are splice variants of the PKM gene that differ by a single exon. Various types of hnRNPs such as hnRNPA1 and hnRNPA2 enter the nucleus during hypoxia conditions and modulate expression such that PKM2 is up-regulated.<ref>{{cite journal | vauthors = Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer AR | title = The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 5 | pages = 1894–9 | date = February 2010 | pmid = 20133837 | pmc = 2838216 | doi = 10.1073/pnas.0914845107 | bibcode = 2010PNAS..107.1894C | doi-access = free }}</ref> Hormones such as [[insulin]] up-regulate expression of PKM2 while hormones like [[Triiodothyronine|tri-iodothyronine]] (T3) and [[glucagon]] aid in down-regulating PKM2.<ref>{{cite journal | vauthors = Iqbal MA, Siddiqui FA, Gupta V, Chattopadhyay S, Gopinath P, Kumar B, Manvati S, Chaman N, Bamezai RN | display-authors = 6 | title = Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2 | journal = Molecular Cancer | volume = 12 | issue = 1 | pages = 72 | date = July 2013 | pmid = 23837608 | pmc = 3710280 | doi = 10.1186/1476-4598-12-72 | doi-access = free }}</ref>

==== Carbohydrate response element binding protein (ChREBP) ====
[[Carbohydrate-responsive element-binding protein|ChREBP]] is a [[transcription factor]] that regulates expression of the L isozyme of pyruvate kinase.<ref name=":0">{{cite journal |vauthors=Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K |date=November 2001 |title=Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=98 |issue=24 |pages=13710–5 |bibcode=2001PNAS...9813710K |doi=10.1073/pnas.231370798 |pmc=61106 |pmid=11698644 |doi-access=free}}</ref> A glucose-sensing module contains domains that are targets for regulatory phosphorylation based on the concentrations of glucose and cAMP, which then control its import into the nucleus.<ref name=":1">{{Cite journal |last1=Ortega-Prieto |first1=Paula |last2=Postic |first2=Catherine |date=2019 |title=Carbohydrate Sensing Through the Transcription Factor ChREBP |journal=Frontiers in Genetics |volume=10 |page=472 |doi=10.3389/fgene.2019.00472 |pmid=31275349 |pmc=6593282 |issn=1664-8021|doi-access=free }}</ref> It may also be further activated by directly binding [[Glucose 6-phosphate|glucose-6-phosphate.]]<ref name=":0" /><ref>{{Cite journal |last1=Richards |first1=Paul |last2=Ourabah |first2=Sarah |last3=Montagne |first3=Jacques |last4=Burnol |first4=Anne-Françoise |last5=Postic |first5=Catherine |last6=Guilmeau |first6=Sandra |date=2017 |title=MondoA/ChREBP: The usual suspects of transcriptional glucose sensing; Implication in pathophysiology |url=https://pubmed.ncbi.nlm.nih.gov/28403938 |journal=Metabolism: Clinical and Experimental |volume=70 |pages=133–151 |doi=10.1016/j.metabol.2017.01.033 |issn=1532-8600 |pmid=28403938}}</ref> Once in the nucleus, its DNA binding domains activate pyruvate kinase transcription.<ref name=":1" /> Therefore, high glucose and low cAMP causes dephosphorylation of [[Carbohydrate-responsive element-binding protein|ChREBP]], which then upregulates expression of pyruvate kinase in the liver.<ref name=":0" />