Ornithine decarboxylase

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Ornithine decarboxylase
1d7k.jpg
Ornithine decarboxylase dimer, Human
Identifiers
EC no. 4.1.1.17
CAS no. 9024-60-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
ornithine decarboxylase
Identifiers
SymbolODC1
NCBI gene 4953
HGNC 8109
OMIM 165640
RefSeq NM_002539
UniProt P11926
Other data
EC number 4.1.1.17
Locus Chr. 2 p25
Search for
Structures Swiss-model
Domains InterPro

The enzyme ornithine decarboxylase (EC 4.1.1.17, ODC) catalyzes the decarboxylation of ornithine (a product of the urea cycle) to form putrescine. This reaction is the committed step in polyamine synthesis. [1] In humans, this protein has 461 amino acids and forms a homodimer. [2]

Contents

In humans, ornithine decarboxylase (ODC) is expressed by the gene ODC1. The protein ODC is sometimes referred to as "ODC1" in research pertaining to humans and mice, but certain species such as Drosophila (dODC2), [3] species of Solanaceae plant family (ODC2), [4] and the lactic acid bacteria Paucilactobacillus wasatchensis (odc2) [5] have been shown to have a second ODC gene.

Reaction mechanism

Lysine 69 on ornithine decarboxylase (ODC) binds the cofactor pyridoxal phosphate to form a Schiff base. [6] 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. [7] This is the first step and the rate-limiting step in humans for the production of polyamines, compounds required for cell division.

Ornithine decarboxylase mechanism.png

Spermidine synthase can then catalyze the conversion of putrescine to spermidine by the attachment of an aminopropyl moiety. [8] Spermidine is a precursor to other polyamines, such as spermine and its structural isomer thermospermine.

Structure

3D crystal structure of ornithine decarboxylase. Ornithine Decarboxylase Publication View.png
3D crystal structure of ornithine decarboxylase.

The active form of ornithine decarboxylase is a homodimer. Each monomer contains a barrel domain, consisting of an alpha-beta barrel, and a sheet domain, composed of two beta-sheets. 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. [1]

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. [1]

Function

The ornithine decarboxylation reaction catalyzed by ornithine decarboxylase is the first and committed step in the synthesis of polyamines, particularly putrescine, spermidine and spermine. Polyamines are important for stabilizing DNA structure, the DNA double strand-break repair pathway and as antioxidants. 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. [10]

Proteasomal degradation

ODC is the most well-characterized cellular protein subject to ubiquitin-independent 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 antizyme. The ODC degradation process is regulated in a negative feedback loop by its reaction products. [11]

Until a report by Sheaff et al. (2000), [12] 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. [13]

Clinical significance

ODC is a transcriptional target of the oncogene Myc [14] 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. [15] Ultraviolet light, [16] asbestos [17] and androgens released by the prostate gland [18] 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, [19] 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 [20] and downregulate tight junction genes. Gap junction genes are involved in communication between carcinogenic cells and tight junction genes act as tumor suppressors. [15]

Mutations of the ODC1 gene have been shown to cause Bachmann-Bupp syndrome (BABS), a rare neurometabolic disorder characterized by global developmental delay, alopecia, macrocephaly, dysmorphic features, and behavioral abnormalities. [21] BABS is typically caused by an autosomal dominant de novo ODC1 variant. [21]

ODC gene expression is induced by a large number of biological stimuli including seizure activity in the brain. [22] Inactivation of ODC by difluoromethylornithine (DMFO, eflornithine) is used to treat cancer and facial hair growth in postmenopausal females.

ODC is also an enzyme indispensable to parasites like Trypanosoma , Giardia , and Plasmodium , a fact exploited by the drug eflornithine. [23]

Immunological significance

In antigen-activated T cells, ODC enzymatic activity increases after activation, which corresponds with increase in polyamine synthesis in T cells after activation. [24] As with ODC and cancer, MYC, also referred to as c-Myc for cellular Myc, is the master regulator of polyamine biosynthesis in T cells. [25]

A 2020 study by Wu et al. using T-cell specific ODC cKO mice showed that T cells can function and proliferate normally in vivo and other polyamine synthesis pathways can compensate for lack of ODC. [26] However, blocking polyamine synthesis via ODC with DMFO and polyamine uptake with AMXT 1501 depleted the polyamine pool and inhibited T-cell proliferation and suppressed T-cell inflammation. [26]

Recent studies have shown the importance of ODC and polyamine synthesis in T helper cell fate commitment. [27] A 2021 study by Puleston et al. showed that TH1 and TH2 cells express higher levels of ODC than regulatory T (Treg) cells and TH17 cells, which corresponded to higher levels of polyamine biosynthesis in TH1 and TH2. [28] A 2021 study by Wagner et al. showed a promotion of a Treg program in Odc1-/- mice. [29] They concluded that polyamine-related enzyme expression was enhanced in pathogenic TH17 and suppressed in Treg cells. [29]

Related Research Articles

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Putrescine</span> Foul-smelling organic chemical compound

Putrescine is an organic compound with the formula (CH2)4(NH2)2. It is a colorless solid that melts near room temperature. It is classified as a diamine. Together with cadaverine, it is largely responsible for the foul odor of putrefying flesh, but also contributes to other unpleasant odors.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Eflornithine</span> Chemical compound

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is taken intravenously or topically. It has also been given orally on at least some rare occasions for the treatment of African trypanosomiasis.

Spermine is a polyamine involved in cellular metabolism that is found in all eukaryotic cells. The precursor for synthesis of spermine is the amino acid ornithine. It is an essential growth factor in some bacteria as well. It is found as a polycation at physiological pH. Spermine is associated with nucleic acids and is thought to stabilize helical structure, particularly in viruses. It functions as an intracellular free radical scavenger to protect DNA from free radical attack. Spermine is the chemical primarily responsible for the characteristic odor of semen.

<span class="mw-page-title-main">Spermidine</span> Chemical compound

Spermidine is a polyamine compound found in ribosomes and living tissues and having various metabolic functions within organisms. It was originally isolated from semen.

<span class="mw-page-title-main">Spermidine synthase</span>

Spermidine synthase is an enzyme that catalyzes the transfer of the propylamine group from S-adenosylmethioninamine to putrescine in the biosynthesis of spermidine. The systematic name is S-adenosyl 3-(methylthio)propylamine:putrescine 3-aminopropyltransferase and it belongs to the group of aminopropyl transferases. It does not need any cofactors. Most spermidine synthases exist in solution as dimers.

<span class="mw-page-title-main">Degron</span> Part of a protein regulating rates of degradation

A degron is a portion of a protein that is important in regulation of protein degradation rates. Known degrons include short amino acid sequences, structural motifs and exposed amino acids located anywhere in the protein. In fact, some proteins can even contain multiple degrons. Degrons are present in a variety of organisms, from the N-degrons first characterized in yeast to the PEST sequence of mouse ornithine decarboxylase. Degrons have been identified in prokaryotes as well as eukaryotes. While there are many types of different degrons, and a high degree of variability even within these groups, degrons are all similar for their involvement in regulating the rate of a protein's degradation. Much like protein degradation, mechanisms are categorized by their dependence or lack thereof on ubiquitin, a small protein involved in proteasomal protein degradation, Degrons may also be referred to as “ubiquitin-dependent" or “ubiquitin-independent".

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

<span class="mw-page-title-main">SpeF leader</span> Cis-acting element

SpeF is a putative cis-acting element identified in several gram negative alpha proteobacteria. It is proposed to be involved in regulating expression of genes involved in polyamide biosynthesis.

<span class="mw-page-title-main">Ornithine decarboxylase antizyme</span>

In molecular biology, Ornithine decarboxylase antizyme (ODC-AZ) is an ornithine decarboxylase inhibitor. It binds to, and destabilises, ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis. ODC is then rapidly degraded. It was first characterized in 1981. The expression of ODC-AZ requires programmed, ribosomal frameshifting which is modulated according to the cellular concentration of polyamines. High levels of polyamines induce a +1 ribosomal frameshift in the translation of mRNA for the antizyme leading to the expression of a full-length protein. At least two forms of ODC-AZ exist in mammals and the protein has been found in Drosophila as well as in Saccharomyces yeast.

<span class="mw-page-title-main">PSMD13</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 13 is an enzyme that in humans is encoded by the PSMD13 gene.

<span class="mw-page-title-main">PSMD11</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 11 is an enzyme that in humans is encoded by the PSMD11 gene.

<span class="mw-page-title-main">SAT1 (gene)</span> Protein-coding gene in the species Homo sapiens

Diamine acetyltransferase 1 is an enzyme that in humans is encoded by the SAT1 gene found on the X chromosome.

<span class="mw-page-title-main">OAZ1</span> Protein-coding gene in humans

Ornithine decarboxylase antizyme is an enzyme that in humans is encoded by the OAZ1 gene.

<span class="mw-page-title-main">PSMD14</span> Protein-coding gene in the species Homo sapiens

26S proteasome non-ATPase regulatory subunit 14, also known as 26S proteasome non-ATPase subunit Rpn11, is an enzyme that in humans is encoded by the PSMD14 gene. This protein is one of the 19 essential subunits of the complete assembled 19S proteasome complex. Nine subunits Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, SEM1, and Rpn12 form the lid sub complex of the 19S regulatory particle of the proteasome complex.

<span class="mw-page-title-main">AZIN1</span> Protein-coding gene in the species Homo sapiens

Antizyme inhibitor 1 is a protein that in humans is encoded by the AZIN1 gene.

<span class="mw-page-title-main">OAZ2</span> Enzyme

Ornithine decarboxylase antizyme 2 is an enzyme that in humans is encoded by the OAZ2 gene.

A polyamine is an organic compound having more than two amino groups. Alkyl polyamines occur naturally, but some are synthetic. Alkylpolyamines are colorless, hygroscopic, and water soluble. Near neutral pH, they exist as the ammonium derivatives. Most aromatic polyamines are crystalline solids at room temperature.

Bachmann-Bupp Syndrome (BABS) is a rare genetic disorder linked to mutations in the ODC1 gene. It is caused by 3' end mutations of the ODC1 gene which produces C-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. This prevents ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC. This leads to an increased conversion of ornithine to putrescine, causing an accumulation of putrescine. So, if the ODC protein is not properly degraded leading to an accumulation ODC and later putrescine, it causes many gain-of-function mutations. This leads to a wide variety of symptoms which is why misdiagnosis is often a reality. Penetrance of the pathogenic variants for the ODC1 gene is believed to be 100%.

References

  1. 1 2 3 Kern AD, Oliveira MA, Coffino P, Hackert ML (May 1999). "Structure of mammalian ornithine decarboxylase at 1.6 A resolution: stereochemical implications of PLP-dependent amino acid decarboxylases". Structure. 7 (5): 567–581. doi: 10.1016/S0969-2126(99)80073-2 . PMID   10378276.
  2. ↑ Pegg AE (May 2006). "Regulation of ornithine decarboxylase". The Journal of Biological Chemistry. 281 (21): 14529–14532. doi: 10.1074/jbc.R500031200 . PMID   16459331.
  3. ↑ Rom E, Kahana C (1993). "Isolation and characterization of the Drosophila ornithine decarboxylase locus: evidence for the presence of two transcribed ODC genes in the Drosophila genome". DNA and Cell Biology. 12 (6): 499–508. doi:10.1089/dna.1993.12.499. PMID   8329117.
  4. ↑ Qin X, Chetelat RT (May 2021). "Ornithine decarboxylase genes contribute to S-RNase-independent pollen rejection". Plant Physiology. 186 (1): 452–468. doi:10.1093/plphys/kiab062. PMC   8154068 . PMID   33576789.
  5. ↑ Berthoud H, Wechsler D, Irmler S (2022-03-03). "Production of Putrescine and Cadaverine by Paucilactobacillus wasatchensis". Frontiers in Microbiology. 13: 842403. doi: 10.3389/fmicb.2022.842403 . PMC   8928434 . PMID   35308356.
  6. ↑ Oliveira EF, Cerqueira NM, Fernandes PA, Ramos MJ (October 2011). "Mechanism of formation of the internal aldimine in pyridoxal 5'-phosphate-dependent enzymes". Journal of the American Chemical Society. 133 (39): 15496–15505. doi:10.1021/ja204229m. PMID   21854048.
  7. ↑ Brooks HB, Phillips MA (December 1997). "Characterization of the reaction mechanism for Trypanosoma brucei ornithine decarboxylase by multiwavelength stopped-flow spectroscopy". Biochemistry. 36 (49): 15147–15155. doi:10.1021/bi971652b. PMID   9398243.
  8. ↑ Teti D, Visalli M, McNair H (December 2002). "Analysis of polyamines as markers of (patho)physiological conditions". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 781 (1–2): 107–149. doi:10.1016/S1570-0232(02)00669-4. PMID   12450656.
  9. ↑ PDB: 1d7k ​; Almrud JJ, Oliveira MA, Kern AD, Grishin NV, Phillips MA, Hackert ML (January 2000). "Crystal structure of human ornithine decarboxylase at 2.1 A resolution: structural insights to antizyme binding". Journal of Molecular Biology. 295 (1): 7–16. doi:10.1006/jmbi.1999.3331. PMID   10623504.; rendered via PyMOL.
  10. ↑ Pendeville H, Carpino N, Marine JC, Takahashi Y, Muller M, Martial JA, Cleveland JL (October 2001). "The ornithine decarboxylase gene is essential for cell survival during early murine development". Molecular and Cellular Biology. 21 (19): 6549–6558. doi:10.1128/MCB.21.19.6549-6558.2001. PMC   99801 . PMID   11533243.
  11. ↑ Zhang M, Pickart CM, Coffino P (April 2003). "Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate". The EMBO Journal. 22 (7): 1488–1496. doi:10.1093/emboj/cdg158. PMC   152902 . PMID   12660156.
  12. ↑ Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM, Clurman BE (February 2000). "Proteasomal turnover of p21Cip1 does not require p21Cip1 ubiquitination". Molecular Cell. 5 (2): 403–410. doi: 10.1016/S1097-2765(00)80435-9 . PMID   10882081.
  13. ↑ Verma R, Deshaies RJ (May 2000). "A proteasome howdunit: the case of the missing signal". Cell. 101 (4): 341–344. doi: 10.1016/S0092-8674(00)80843-0 . PMID   10830160. S2CID   18425370.
  14. ↑ Bello-Fernandez C, Packham G, Cleveland JL (August 1993). "The ornithine decarboxylase gene is a transcriptional target of c-Myc". Proceedings of the National Academy of Sciences of the United States of America. 90 (16): 7804–7808. Bibcode:1993PNAS...90.7804B. doi: 10.1073/pnas.90.16.7804 . PMC   47231 . PMID   8356088.
  15. 1 2 Gerner EW, Meyskens FL (October 2004). "Polyamines and cancer: old molecules, new understanding". Nature Reviews. Cancer. 4 (10): 781–792. doi:10.1038/nrc1454. PMID   15510159. S2CID   37647479.
  16. ↑ Ahmad N, Gilliam AC, Katiyar SK, O'Brien TG, Mukhtar H (September 2001). "A definitive role of ornithine decarboxylase in photocarcinogenesis". The American Journal of Pathology. 159 (3): 885–892. doi:10.1016/S0002-9440(10)61764-6. PMC   1850478 . PMID   11549581.
  17. ↑ Marsh JP, Mossman BT (January 1991). "Role of asbestos and active oxygen species in activation and expression of ornithine decarboxylase in hamster tracheal epithelial cells". Cancer Research. 51 (1): 167–173. PMID   1846307.
  18. ↑ Crozat A, Palvimo JJ, Julkunen M, Jänne OA (March 1992). "Comparison of androgen regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase gene expression in rodent kidney and accessory sex organs". Endocrinology. 130 (3): 1131–1144. doi:10.1210/endo.130.3.1537280. PMID   1537280.
  19. ↑ Meyskens FL, Gerner EW (May 1999). "Development of difluoromethylornithine (DFMO) as a chemoprevention agent". Clinical Cancer Research. 5 (5): 945–951. PMID   10353725.
  20. ↑ Shore L, McLean P, Gilmour SK, Hodgins MB, Finbow ME (July 2001). "Polyamines regulate gap junction communication in connexin 43-expressing cells". The Biochemical Journal. 357 (Pt 2): 489–495. doi:10.1042/0264-6021:3570489. PMC   1221976 . PMID   11439099.
  21. 1 2 Bupp C, Michael J, VanSickle E, Rajasekaran S, Bachmann AS (1993). "Bachmann-Bupp Syndrome". In Adam MP, Mirzaa GM, Pagon RA, Wallace SE (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   36007106 . Retrieved 2023-06-28.
  22. ↑ Herberg LJ, Rose IC, de Belleroche JS, Mintz M (March 1992). "Ornithine decarboxylase induction and polyamine synthesis in the kindling of seizures: the effect of alpha-difluoromethylornithine". Epilepsy Research. 11 (1): 3–7. doi:10.1016/0920-1211(92)90015-L. PMID   1563337. S2CID   1221264.
  23. ↑ Heby O, Persson L, Rentala M (August 2007). "Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas' disease, and leishmaniasis". Amino Acids. 33 (2): 359–366. doi:10.1007/s00726-007-0537-9. PMID   17610127. S2CID   26273053.
  24. ↑ Hesterberg RS, Cleveland JL, Epling-Burnette PK (March 2018). "Role of Polyamines in Immune Cell Functions". Medical Sciences. 6 (1): 22. doi: 10.3390/medsci6010022 . PMC   5872179 . PMID   29517999.
  25. ↑ Miller DM, Thomas SD, Islam A, Muench D, Sedoris K (October 2012). "c-Myc and cancer metabolism". Clinical Cancer Research. 18 (20): 5546–5553. doi:10.1158/1078-0432.CCR-12-0977. PMC   3505847 . PMID   23071356.
  26. 1 2 Wu R, Chen X, Kang S, Wang T, Gnanaprakasam JR, Yao Y, et al. (December 2020). "De novo synthesis and salvage pathway coordinately regulate polyamine homeostasis and determine T cell proliferation and function". Science Advances. 6 (51). Bibcode:2020SciA....6.4275W. doi:10.1126/sciadv.abc4275. PMC   7744078 . PMID   33328226.
  27. ↑ Shi H, Chi H (August 2021). "Polyamine: A metabolic compass for T helper cell fate direction". Cell. 184 (16): 4109–4112. doi: 10.1016/j.cell.2021.07.012 . PMID   34358466.
  28. ↑ Puleston DJ, Baixauli F, Sanin DE, Edwards-Hicks J, Villa M, Kabat AM, et al. (August 2021). "Polyamine metabolism is a central determinant of helper T cell lineage fidelity". Cell. 184 (16): 4186–4202.e20. doi:10.1016/j.cell.2021.06.007. PMC   8358979 . PMID   34216540.
  29. 1 2 Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, et al. (August 2021). "Metabolic modeling of single Th17 cells reveals regulators of autoimmunity". Cell. 184 (16): 4168–4185.e21. doi:10.1016/j.cell.2021.05.045. PMC   8621950 . PMID   34216539.
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