Editing Metabolism (section)

==Regulation and control==
{{further|Metabolic pathway|Metabolic control analysis|Hormone|Regulatory enzymes|Cell signaling}}
As the environments of most organisms are constantly changing, the reactions of metabolism must be finely [[Control theory|regulated]] to maintain a constant set of conditions within cells, a condition called [[homeostasis]].<ref>{{cite journal | vauthors = Albert R | title = Scale-free networks in cell biology | journal = Journal of Cell Science | volume = 118 | issue = Pt 21 | pages = 4947–57 | date = November 2005 | pmid = 16254242 | doi = 10.1242/jcs.02714 | arxiv = q-bio/0510054 | s2cid = 3001195 | bibcode = 2005q.bio....10054A }}</ref><ref>{{cite journal | vauthors = Brand MD | title = Regulation analysis of energy metabolism | journal = The Journal of Experimental Biology | volume = 200 | issue = Pt 2 | pages = 193–202 | date = January 1997 | doi = 10.1242/jeb.200.2.193 | pmid = 9050227 | bibcode = 1997JExpB.200..193B | url = http://jeb.biologists.org/cgi/reprint/200/2/193 | access-date = 12 March 2007 | archive-date = 29 March 2007 | archive-url = https://web.archive.org/web/20070329202116/http://jeb.biologists.org/cgi/reprint/200/2/193 | url-status = live }}</ref> Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.<ref>{{cite journal | vauthors = Soyer OS, Salathé M, Bonhoeffer S | title = Signal transduction networks: topology, response and biochemical processes | journal = Journal of Theoretical Biology | volume = 238 | issue = 2 | pages = 416–25 | date = January 2006 | pmid = 16045939 | doi = 10.1016/j.jtbi.2005.05.030 | bibcode = 2006JThBi.238..416S }}</ref> Two closely linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the ''regulation'' of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the ''control'' exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the [[flux]] through the pathway).<ref name="Salter-1994">{{cite journal | vauthors = Salter M, Knowles RG, Pogson CI | title = Metabolic control | journal = Essays in Biochemistry | volume = 28 | pages = 1–12 | year = 1994 | pmid = 7925313 }}</ref> For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.<ref>{{cite journal | vauthors = Westerhoff HV, Groen AK, Wanders RJ | title = Modern theories of metabolic control and their applications (review) | journal = Bioscience Reports | volume = 4 | issue = 1 | pages = 1–22 | date = January 1984 | pmid = 6365197 | doi = 10.1007/BF01120819 | s2cid = 27791605 }}</ref>
[[File:Insulin glucose metabolism ZP.svg|thumb|right|upright=1.35|Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the [[plasma membrane]] and influx of glucose (3), [[glycogen]] synthesis (4), [[glycolysis]] (5) and [[fatty acid]] synthesis (6).<ref name="q459">{{cite book | last=Chouhan | first=Raje | last2=Goswami | first2=Shilpi | last3=Bajpai | first3=Anil Kumar | title=Nanostructures for Oral Medicine | chapter=Recent advancements in oral delivery of insulin: from challenges to solutions | publisher=Elsevier | date=2017 | isbn=978-0-323-47720-8 | doi=10.1016/b978-0-323-47720-8.00016-x | url=https://linkinghub.elsevier.com/retrieve/pii/B978032347720800016X | access-date=2025-04-17 | page=435–465}}</ref>]]

There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the [[flux]] through the pathway to compensate.<ref name="Salter-1994"/> This type of regulation often involves [[allosteric regulation]] of the activities of multiple enzymes in the pathway.<ref>{{cite journal | vauthors = Fell DA, Thomas S | title = Physiological control of metabolic flux: the requirement for multisite modulation | journal = The Biochemical Journal | volume = 311 | issue = Pt 1 | pages = 35–9 | date = October 1995 | pmid = 7575476 | pmc = 1136115 | doi = 10.1042/bj3110035 }}</ref> Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of water-soluble messengers such as [[hormone]]s and [[growth factor]]s and are detected by specific [[receptor (biochemistry)|receptors]] on the cell surface.<ref>{{cite journal | vauthors = Hendrickson WA | title = Transduction of biochemical signals across cell membranes | journal = Quarterly Reviews of Biophysics | volume = 38 | issue = 4 | pages = 321–30 | date = November 2005 | pmid = 16600054 | doi = 10.1017/S0033583506004136 | s2cid = 39154236 }}</ref> These signals are then transmitted inside the cell by [[second messenger system]]s that often involved the [[phosphorylation]] of proteins.<ref>{{cite journal | vauthors = Cohen P | title = The regulation of protein function by multisite phosphorylation--a 25 year update | journal = Trends in Biochemical Sciences | volume = 25 | issue = 12 | pages = 596–601 | date = December 2000 | pmid = 11116185 | doi = 10.1016/S0968-0004(00)01712-6 }}</ref>

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone [[insulin]].<ref>{{cite journal | vauthors = Lienhard GE, Slot JW, James DE, Mueckler MM | title = How cells absorb glucose | journal = Scientific American | volume = 266 | issue = 1 | pages = 86–91 | date = January 1992 | pmid = 1734513 | doi = 10.1038/scientificamerican0192-86 | bibcode = 1992SciAm.266a..86L }}</ref> Insulin is produced in response to rises in [[blood sugar|blood glucose levels]]. Binding of the hormone to [[insulin receptor]]s on cells then activates a cascade of [[protein kinase]]s that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and [[glycogen]].<ref>{{cite journal | vauthors = Roach PJ | title = Glycogen and its metabolism | journal = Current Molecular Medicine | volume = 2 | issue = 2 | pages = 101–20 | date = March 2002 | pmid = 11949930 | doi = 10.2174/1566524024605761 }}</ref> The metabolism of glycogen is controlled by activity of [[phosphorylase]], the enzyme that breaks down glycogen, and [[glycogen synthase]], the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating [[phosphatase|protein phosphatases]] and producing a decrease in the phosphorylation of these enzymes.<ref>{{cite journal | vauthors = Newgard CB, Brady MJ, O'Doherty RM, Saltiel AR | title = Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1 | journal = Diabetes | volume = 49 | issue = 12 | pages = 1967–77 | date = December 2000 | pmid = 11117996 | doi = 10.2337/diabetes.49.12.1967 | url = http://diabetes.diabetesjournals.org/cgi/reprint/49/12/1967.pdf | doi-access = free | access-date = 25 March 2007 | archive-date = 19 June 2007 | archive-url = https://web.archive.org/web/20070619211503/http://diabetes.diabetesjournals.org/cgi/reprint/49/12/1967.pdf | url-status = live }}</ref>