View source for Ornithine decarboxylase

{{enzyme
| Name = ornithine decarboxylase
| EC_number = 4.1.1.17
| CAS_number = 9024-60-6
| IUBMB_EC_number = 4/1/1/17
| GO_code = 0004586
| image = 1d7k.jpg
| width = 270
| caption = Ornithine decarboxylase dimer, Human
}}
{{Infobox protein
   |Name=ornithine decarboxylase
   |image=
   |caption=
   |Symbol=ODC1 
   |AltSymbols=
   |HGNCid=8109
   |Chromosome=2
   |Arm=p
   |Band=25
   |LocusSupplementaryData=
   |ECnumber=4.1.1.17
   |OMIM=165640
   |EntrezGene=4953
   |RefSeq=NM_002539
   |UniProt=P11926
   |PDB=
}}
The enzyme '''ornithine decarboxylase''' (ODC) catalyzes the [[decarboxylation]] of [[ornithine]] (a product of the [[urea cycle]]) to form [[putrescine]]. This reaction is the [[committed step]] in [[polyamine]] synthesis.<ref name="pmid10378276">{{cite journal |vauthors=Kern AD, Oliveira MA, Coffino P, Hackert ML |title=Structure of mammalian ornithine decarboxylase at 1.6 A resolution: stereochemical implications of PLP-dependent amino acid decarboxylases |journal=Structure |volume=7 |issue=5 |pages=567–81 |date=May 1999 |pmid=10378276 |doi= 10.1016/S0969-2126(99)80073-2|url=}}</ref> In humans, this protein has 461 [[amino acid]]s and forms a [[homodimer]].

== Reaction mechanism ==

[[Lysine]] 69 on ornithine decarboxylase (ODC) binds the [[Cofactor (biochemistry)|cofactor]] [[pyridoxal phosphate]] to form a [[Schiff base]]. Ornithine displaces the lysine to form a Schiff base attached to orthonine, which decarboxylates to form a [[quinoid]] intermediate. This intermediate rearranges to form a Schiff base attached to [[putrescine]], which is attacked by [[lysine]] to release putrescine product and reform PLP-bound ODC.<ref name="pmid9398243">{{cite journal |vauthors=Brooks HB, Phillips MA |title=Characterization of the reaction mechanism for Trypanosoma brucei ornithine decarboxylase by multiwavelength stopped-flow spectroscopy |journal=Biochemistry |volume=36 |issue=49 |pages=15147–55 |date=December 1997 |pmid=9398243 |doi=10.1021/bi971652b |url=}}</ref>

[[Image:ornithine decarboxylase mechanism.png|900px|border|alt=ornithine decarboxylase mechanism|Hypothesized ornithine decarboxylase mechanism.]]

This is the first step and the rate-limiting step in humans for the production of [[polyamine]]s, compounds required for [[cell division]].

==Structure==
[[image:Ornithine Decarboxylase Publication View.png|270px|thumb|right|3D crystal structure of ornithine decarboxylase.<ref name="pmid10623504">{{PDB|1d7k}}; {{cite journal |vauthors=Almrud JJ, Oliveira MA, Kern AD, Grishin NV, Phillips MA, Hackert ML | title = Crystal structure of human ornithine decarboxylase at 2.1 A resolution: structural insights to antizyme binding | journal = J. Mol. Biol. | volume = 295 | issue = 1 | pages = 7–16 |date=January 2000 | pmid = 10623504| doi = 10.1006/jmbi.1999.3331| url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WK7-45F4V3C-5P&_user=483702&_coverDate=01%2F07%2F2000&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1468011589&_rerunOrigin=google&_acct=C000022720&_version=1&_urlVersion=0&_userid=483702&md5=1cea1cd3d0bf40355b774bdf274fe9e0&searchtype=a| issn = }}; rendered via [http://pymol.sourceforge.net PyMOL].</ref>]]

The active form of ornithine decarboyxlase is a [[homodimer]]. Each [[monomer]] contains a barrel domain, consisting of an [[alpha-beta barrel]], and a sheet domain, composed of two [[beta-sheet]]s. The domains are connected by loops. The monomers connect to each other via interactions between the barrel of one monomer and the sheet of the other. Binding between monomers is relatively weak, and ODC interconverts rapidly between monomeric and dimeric forms in the cell.<ref name="pmid10378276"/>

The [[pyridoxal phosphate]] cofactor binds lysine 69 at the [[C-terminus]] end of the barrel domain.  The [[active site]] is at the interface of the two domains, in a cavity formed by loops from both monomers.<ref name="pmid10378276"/>

==Function==

The ornithine decarboxylation reaction catalyzed by ornithine decarboxylase is the first and [[committed step]] in the synthesis of [[polyamine]]s, particularly [[putrescine]], [[spermidine]] and [[spermine]].  Polyamines are important for stabilizing [[DNA]] structure, the DNA [[DNA repair#Double-strand breaks|double strand-break repair]] pathway and as [[antioxidant]]s. Therefore, ornithine decarboxylase is an essential enzyme for cell growth, producing the polyamines necessary to stabilize newly synthesized DNA. Lack of ODC causes cell [[apoptosis]] in embryonic mice, induced by DNA damage.<ref name="pmid11533243">{{cite journal  |vauthors=Pendeville H, Carpino N, Marine JC, etal |title=The ornithine decarboxylase gene is essential for cell survival during early murine development |journal=Mol. Cell. Biol. |volume=21 |issue=19 |pages=6549–58 |date=October 2001 |pmid=11533243 |pmc=99801 |doi= 10.1128/MCB.21.19.6549-6558.2001|url=http://orbi.ulg.ac.be/bitstream/2268/14993/1/The%20ornithine%20decarboxylase%20gene%20is%20essential%20for%20cell%20survival%20during%20early%20murine%20development.pdf}}</ref>

== Proteasomal degradation==

ODC is the most well-characterized cellular protein subject to [[ubiquitin]]-independent [[proteasome|proteasomal]] degradation. Although most proteins must first be tagged with multiple [[ubiquitin]] molecules before they are bound and degraded by the [[proteasome]], ODC degradation is instead mediated by several recognition sites on the protein and its accessory factor [[Ornithine decarboxylase antizyme|antizyme]]. The ODC degradation process is regulated in a [[negative feedback loop]] by its reaction products.<ref name="pmid12660156">{{cite journal |vauthors=Zhang M, Pickart CM, Coffino P | title = Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate | journal = EMBO J. | volume = 22 | issue = 7 | pages = 1488–96 |date=April 2003 | pmid = 12660156 | pmc = 152902 | doi = 10.1093/emboj/cdg158 | url = | issn = }}</ref>

Until a report by Sheaff et al. (2000),<ref name="pmid10882081">{{cite journal |vauthors=Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM, Clurman BE | title = Proteasomal turnover of p21Cip1 does not require p21Cip1 ubiquitination | journal = Mol. Cell | volume = 5 | issue = 2 | pages = 403–10 |date=February 2000 | pmid = 10882081 | doi = 10.1016/S1097-2765(00)80435-9| url = | issn = }}</ref> which demonstrated that the cyclin-dependent kinase (Cdk) inhibitor [[p21Cip1]] is also degraded by the proteasome in a ubiquitin-independent manner, ODC was the only clear example of ubiquitin-independent proteasomal degradation.<ref name="pmid10830160">{{cite journal |vauthors=Verma R, Deshaies RJ | title = A proteasome howdunit: the case of the missing signal | journal = Cell | volume = 101 | issue = 4 | pages = 341–4 |date=May 2000 | pmid = 10830160 | doi = 10.1016/S0092-8674(00)80843-0| url = | issn = }}</ref>

== Clinical significance ==

ODC is a transcriptional target of the [[oncogene]] [[Myc]]<ref name="pmid8356088">{{cite journal |vauthors=Bello-Fernandez C, Packham G, Cleveland JL |title=The ornithine decarboxylase gene is a transcriptional target of c-Myc |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=16 |pages=7804–8 |date=August 1993 |pmid=8356088 |pmc=47231 |doi= 10.1073/pnas.90.16.7804|url=}}</ref> and is upregulated in a wide variety of cancers. The polyamine products of the pathway initialized by ODC are associated with increased cell growth and reduced [[apoptosis]].<ref name="pmid15510159">{{cite journal |vauthors=Gerner EW, Meyskens FL |title=Polyamines and cancer: old molecules, new understanding |journal=Nat. Rev. Cancer |volume=4 |issue=10 |pages=781–92 |date=October 2004 |pmid=15510159 |doi=10.1038/nrc1454 |url=}}</ref> [[Ultraviolet light]],<ref name="pmid11549581">{{cite journal |vauthors=Ahmad N, Gilliam AC, Katiyar SK, O'Brien TG, Mukhtar H |title=A definitive role of ornithine decarboxylase in photocarcinogenesis |journal=Am. J. Pathol. |volume=159 |issue=3 |pages=885–92 |date=September 2001 |pmid=11549581 |pmc=1850478 |doi= 10.1016/S0002-9440(10)61764-6|url=}}</ref> [[asbestos]]<ref name="pmid1846307">{{cite journal |vauthors=Marsh JP, Mossman BT |title=Role of asbestos and active oxygen species in activation and expression of ornithine decarboxylase in hamster tracheal epithelial cells |journal=Cancer Res. |volume=51 |issue=1 |pages=167–73 |date=January 1991 |pmid=1846307 |doi= |url=}}</ref> and [[androgens]] released by the [[prostate gland]]<ref name="pmid1537280">{{cite journal |vauthors=Crozat A, Palvimo JJ, Julkunen M, Jänne OA |title=Comparison of androgen regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase gene expression in rodent kidney and accessory sex organs |journal=Endocrinology |volume=130 |issue=3 |pages=1131–44 |date=March 1992 |pmid=1537280 |doi= 10.1210/en.130.3.1131|url=}}</ref> are all known to induce increased ODC activity associated with cancer. Inhibitors of ODC such as [[eflornithine]] have been shown to effectively reduce cancers in animal models,<ref name="pmid10353725">{{cite journal |vauthors=Meyskens FL, Gerner EW |title=Development of difluoromethylornithine (DFMO) as a chemoprevention agent |journal=Clin. Cancer Res. |volume=5 |issue=5 |pages=945–51 |date=May 1999 |pmid=10353725 |doi= |url=}}</ref> and drugs targeting ODC are being tested for potential clinical use.
The mechanism by which ODC promotes [[carcinogenesis]] is complex and not entirely known. Along with their direct effect on DNA stability, polyamines also upregulate [[gap junction]] genes<ref name="pmid11439099">{{cite journal |vauthors=Shore L, McLean P, Gilmour SK, Hodgins MB, Finbow ME |title=Polyamines regulate gap junction communication in connexin 43-expressing cells |journal=Biochem. J. |volume=357 |issue=Pt 2 |pages=489–95 |date=July 2001 |pmid=11439099 |pmc=1221976 |doi= 10.1042/0264-6021:3570489|url=}}</ref> and downregulate [[tight junction]] genes. Gap junction genes are involved in communication between carcinogenic cells and tight junction genes act as tumor suppressors.<ref name="pmid15510159"/>

ODC gene expression is induced by a large number of biological stimuli including [[seizure]] activity in the brain.<ref name="pmid1563337">{{cite journal |vauthors=Herberg LJ, Rose IC, de Belleroche JS, Mintz M |title=Ornithine decarboxylase induction and polyamine synthesis in the kindling of seizures: the effect of alpha-difluoromethylornithine |journal=Epilepsy Res. |volume=11 |issue=1 |pages=3–7 |year=1992 |pmid=1563337|doi=10.1016/0920-1211(92)90015-L}}</ref> Inactivation of ODC by difluoromethylornithine ([[eflornithine]]) is used to treat [[cancer]] and facial hair growth in postmenopausal females.

ODC is also an enzyme indispensable to [[parasitism|parasites]] like [[trypanosoma]], [[giardia]], and [[plasmodium]], a fact exploited by the drug [[eflornithine]].<ref name="pmid17610127">{{cite journal |vauthors=Heby O, Persson L, Rentala M |title=Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas' disease, and leishmaniasis |journal=Amino Acids |volume=33 |issue=2 |pages=359–66 |date=August 2007 |pmid=17610127 |doi=10.1007/s00726-007-0537-9 |url=}}</ref>

== References ==
{{reflist|2}}

== External links ==
* [http://herkules.oulu.fi/isbn9514266315/html/ Ornithine decarboxylase at herkules.oulu.fi]
* {{MeshName|Ornithine+decarboxylase}}

{{Amino acid metabolism enzymes}}
{{Carbon-carbon lyases}}
{{Enzymes}}
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[[Category:EC 4.1.1]]