Editing Pentose phosphate pathway

{{Short description|Series of interconnected biochemical reactions}}
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[[File:Pentose phosphate pathway en.svg|thumb|right|400px|class=skin-invert-image|The pentose phosphate pathway]]
The '''pentose phosphate pathway''' (also called the '''phosphogluconate pathway''' and the '''hexose monophosphate shunt''' or '''HMP shunt''') is a [[metabolic pathway]] parallel to [[glycolysis]].<ref name="Alfarouk 2020">{{cite journal |last1=Alfarouk |first1=Khalid O. |last2=Ahmed |first2=Samrein B. M. |last3=Elliott |first3=Robert L. |display-authors=etal |title=The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH |journal=Metabolites |date=2020 |volume=10 |page=285 |doi=10.3390/metabo10070285 |pmid=32664469 |pmc=7407102 |doi-access=free }}</ref> It generates [[Nicotinamide adenine dinucleotide phosphate|NADPH]] and [[pentose]]s (five-[[carbon]] [[sugar]]s) as well as [[ribose 5-phosphate]], a precursor for the synthesis of [[nucleotides]].<ref name="Alfarouk 2020" /> While the pentose phosphate pathway does involve oxidation of [[glucose]], its primary role is [[anabolism|anabolic]] rather than [[catabolism|catabolic]]. The pathway is especially important in [[red blood cell]]s (erythrocytes). The reactions of the pathway were elucidated in the early 1950s by [[Bernard Horecker]] and co-workers.<ref>{{cite journal | title= The enzymatic conversion of 6-phosphogluconate to ribulose-5-phosphate and ribose-5-phosphate|journal = J. Biol. Chem. | last1 = Horecker| first1 = B. L.| last2 = Smyrniotis|first2 =P. Z.|last3= Seegmiller|first3 = J. E.|year = 1951|volume = 193|number = 1 |pages = 383–396|doi = 10.1016/S0021-9258(19)52464-4 |doi-access = free |pmid = 14907726 }}</ref><ref>{{cite journal | journal = J. Biol. Chem.| doi=10.1074/jbc.X200007200 |year = 2002|volume = 277|number =  50| pages = 47965–47971|title = The pentose phosphate pathway|doi-access = free | last1=Horecker | first1=Bernard L. | pmid=12403765 }}</ref>

There are two distinct phases in the pathway. The first is the [[oxidation|oxidative]] phase, in which NADPH is generated, and the second is the non-oxidative [[Chemical synthesis|synthesis]] of five-carbon sugars. For most organisms, the pentose phosphate pathway takes place in the [[cytosol]]; in plants, most steps take place in [[plastid]]s.<ref>{{cite journal|last1=Kruger|first1=Nicholas J|last2=von Schaewen|first2=Antje|title=The oxidative pentose phosphate pathway: structure and organisation|journal=Current Opinion in Plant Biology|date=June 2003|volume=6|issue=3|pages=236–246|doi=10.1016/S1369-5266(03)00039-6|pmid=12753973|bibcode=2003COPB....6..236K }}</ref>

Like [[glycolysis]], the pentose phosphate pathway appears to have a very ancient evolutionary origin. The reactions of this pathway are mostly enzyme catalyzed in modern cells, however, they also occur non-enzymatically under conditions that replicate those of the [[Archean]] ocean, and are catalyzed by [[metal ions]], particularly [[ferrous]] ions (Fe(II)).<ref>{{cite journal|last1=Keller|first1=Markus A.|last2=Turchyn|first2=Alexandra V.|last3=Ralser|first3=Markus|title=Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean|journal=Molecular Systems Biology|date=25 April 2014|volume=10|issue=4|pages=725|doi=10.1002/msb.20145228|url= |pmid=24771084|pmc=4023395}}</ref> This suggests that the origins of the pathway could date back to the prebiotic world.

==Outcome==
The primary results of the pathway are:

*The generation of reducing equivalents, in the form of NADPH, used in reductive biosynthesis reactions within cells (e.g. [[fatty acid synthesis]]).
*Production of [[ribose 5-phosphate]] (R5P), used in the synthesis of [[nucleotide]]s and nucleic acids.
*Production of [[erythrose 4-phosphate]] (E4P) used in the synthesis of [[aromatic amino acid]]s.

Aromatic amino acids, in turn, are precursors for many biosynthetic pathways, including the [[lignin]] in wood.{{Citation needed|date=February 2014}}

Dietary pentose sugars derived from the digestion of nucleic acids may be metabolized through the pentose phosphate pathway, and the carbon skeletons of dietary carbohydrates may be converted into glycolytic/gluconeogenic intermediates.

In mammals, the PPP occurs exclusively in the cytoplasm. In humans, it is found to be most active in the liver, mammary glands, and adrenal cortex.{{Citation needed|date=February 2014}} The PPP is one of the three main ways the body creates molecules with [[reduction (chemistry)|reducing]] power, accounting for approximately 60% of NADPH production in humans.{{Citation needed|date=February 2014}}

One of the uses of NADPH in the cell is to prevent [[oxidative stress]]. It reduces [[glutathione]] via [[glutathione reductase]], which converts reactive H<sub>2</sub>O<sub>2</sub> into H<sub>2</sub>O by [[glutathione peroxidase]]. If absent, the H<sub>2</sub>O<sub>2</sub> would be converted to hydroxyl free radicals by [[Fenton's reagent|Fenton chemistry]], which can attack the cell. Erythrocytes, for example, generate a large amount of NADPH through the pentose phosphate pathway to use in the reduction of glutathione.

[[Hydrogen peroxide]] is also generated for [[phagocytes]] in a process often referred to as a [[respiratory burst]].<ref>{{GeorgiaImmunology|1/cytotox}}</ref>

==Phases==

===Oxidative phase===
In this phase, two molecules of [[NADP]]<sup>+</sup> are reduced to [[NADPH]], utilizing the energy from the conversion of [[glucose-6-phosphate]] into [[ribulose 5-phosphate]].

[[Image: Ox Pentose phosphate pathway.svg|thumb|center|570px|class=skin-invert-image|Oxidative phase of pentose phosphate pathway.<br>
Glucose-6-phosphate&nbsp;('''1'''),&nbsp;6-phosphoglucono-δ-lactone&nbsp;('''2'''),&nbsp;6-phosphogluconate&nbsp;('''3'''),&nbsp;ribulose&nbsp;5-phosphate&nbsp;('''4''')]]

The entire set of reactions can be summarized as follows:

{| class="wikitable"
! Reactants !! Products !! Enzyme !! Description
 |- 
 | [[Glucose 6-phosphate]] + NADP+  || → [[6-phosphoglucono-δ-lactone]] + '''NADPH''' || [[glucose 6-phosphate dehydrogenase]] || [[Dehydrogenation]]. The hydroxyl on carbon 1 of glucose 6-phosphate turns into a carbonyl, generating a lactone, and, in the process, [[NADPH]] is generated.  
 |- 
 | [[6-phosphoglucono-δ-lactone]] + H<sub>2</sub>O  || → [[6-phosphogluconate]] + H<sup>+</sup> || [[6-phosphogluconolactonase]] || [[Hydrolysis]]  
 |- 
 | [[6-phosphogluconate]] + NADP<sup>+</sup>  || → [[ribulose 5-phosphate]] + '''NADPH''' + CO<sub>2</sub> || [[6-phosphogluconate dehydrogenase]] ||  Oxidative [[decarboxylation]]. NADP<sup>+</sup> is the electron acceptor, generating another molecule of [[NADPH]], a CO<sub>2</sub>, and [[ribulose 5-phosphate]]. 
 |- 
 |}

The overall reaction for this process is:
:Glucose 6-phosphate + 2 NADP<sup>+</sup> + H<sub>2</sub>O → ribulose 5-phosphate + 2 NADPH + 2 H<sup>+</sup> + CO<sub>2</sub>

===Non-oxidative phase===
[[File:Nichtox Pentosephosphatweg.png|thumb|center|600px|class=skin-invert-image|The pentose phosphate pathway's nonoxidative phase]]

{| class="wikitable"
! Reactants !! Products !! Enzymes
 |- 
 | [[ribulose 5-phosphate]]  || → [[ribose 5-phosphate]]  || [[ribose-5-phosphate isomerase]]
 |- 
 | [[ribulose 5-phosphate]]  || → [[xylulose 5-phosphate]] || [[Phosphopentose epimerase|ribulose 5-phosphate 3-epimerase]]
 |- 
 | [[xylulose 5-phosphate]] + [[ribose 5-phosphate]]  || → [[glyceraldehyde 3-phosphate]] + [[sedoheptulose 7-phosphate]] || [[transketolase]] 
 |- 
 | [[sedoheptulose 7-phosphate]] + [[glyceraldehyde 3-phosphate]]  || → [[erythrose 4-phosphate]] + [[fructose 6-phosphate]] || [[transaldolase]]
 |- 
 | [[xylulose 5-phosphate]] + [[erythrose 4-phosphate]] ||  → [[glyceraldehyde 3-phosphate]] + [[fructose 6-phosphate]] || [[transketolase]]
|}

Net reaction:
3 ribulose-5-phosphate → 1 ribose-5-phosphate + 2 xylulose-5-phosphate → 2 fructose-6-phosphate + glyceraldehyde-3-phosphate

===Regulation===

[[Glucose-6-phosphate dehydrogenase]] is the rate-controlling enzyme of this pathway{{Citation needed|date=October 2022}}. It is [[allosteric]]ally stimulated by NADP<sup>+</sup> and strongly inhibited by [[NADPH]].<ref>{{cite book |author1=Voet Donald |author1-link=Donald Voet |author2=Voet Judith G |author-link2=Judith G. Voet |page=894 |date=2011 |title=Biochemistry |publisher=John Wiley & Sons |edition=4th |isbn=978-0-470-57095-1}}</ref> The ratio of NADPH:NADP<sup>+</sup> is the primary mode of regulation for the enzyme and is normally about 100:1 in liver cytosol{{Citation needed|date=February 2014}}. This makes the cytosol a highly-reducing environment. An NADPH-utilizing pathway forms NADP<sup>+</sup>, which stimulates [[Glucose-6-phosphate dehydrogenase]] to produce more NADPH.  This step is also inhibited by [[acetyl CoA]].{{Citation needed|date=February 2014}}

[[G6PD]] activity is also post-translationally regulated by cytoplasmic deacetylase [[SIRT2]]. SIRT2-mediated deacetylation and activation of G6PD stimulates oxidative branch of PPP to supply cytosolic [[NADPH]] to counteract [[oxidative damage]] or support [[lipogenesis|''de novo'' lipogenesis]].<ref>{{Cite journal|title = Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress|vauthors=Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, Ling ZQ, Hu FJ, Sun YP, Zhang JY, Yang C, Yang Y, Xiong Y, Guan KL, Ye D |date = June 2014|journal = EMBO Journal|doi = 10.1002/embj.201387224|pmid = 24769394|volume=33|issue=12 |pages=1304–20|pmc=4194121}}</ref><ref name="Xu_2016">{{cite journal | vauthors = Xu SN, Wang TS, Li X, Wang YP | title = SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation | journal = Sci Rep | volume = 6 | pages = 32734| date = Sep 2016 | pmid = 27586085  | doi = 10.1038/srep32734 | pmc=5009355| bibcode = 2016NatSR...632734X }}</ref>

==Erythrocytes==

Several deficiencies in the level of activity (not function) of glucose-6-phosphate dehydrogenase have been observed to be associated with resistance to the malarial parasite ''[[Plasmodium falciparum]]'' among individuals of Mediterranean and African descent. The basis for this resistance may be a weakening of the red cell membrane (the erythrocyte is the host cell for the parasite) such that it cannot sustain the parasitic life cycle long enough for productive growth.<ref>{{cite journal |vauthors=Cappadoro M, Giribaldi G, O'Brien E, etal |title=Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency |journal=Blood |volume=92 |issue=7 |pages=2527–34 |date=October 1998 |doi=10.1182/blood.V92.7.2527 |pmid=9746794 |doi-access=free }}</ref>

==See also==
* [[Glucose-6-phosphate dehydrogenase deficiency|G6PD deficiency]] – A hereditary disease that disrupts the pentose phosphate pathway
* [[RNA]]
* [[Thiamine deficiency]]
* [[Frank Dickens (biochemist)|Frank Dickens FRS]]

==References==
<references/>

==External links==
*[http://homepage.ufp.pt/pedros/bq/ppp.htm The chemical logic behind the pentose phosphate pathway]
*{{MeshName|Pentose+Phosphate+Pathway}}
*[http://www.genome.jp/dbget-bin/www_bget?path:hsa00030 Pentose phosphate pathway Map – Homo sapiens]

{{Carbohydrate metabolism}}
{{MetabolismMap}}
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{{Pentose phosphate pathway intermediates}}

[[Category:Pentose phosphate pathway| ]]