Structural Basis of Binding and Inhibition of Ornithine Decarboxylase by 1-amino-oxy-3-aminopropane

Overview

Journal Biochem J

Specialty Biochemistry

Date 2021 Nov 19

PMID 34796899

Citations 4

Authors

X Edward Zhou

Kelly Suino-Powell

Chad R Schultz

Bilal Aleiwi

Joseph S Brunzelle

Jared Lamp

Irving E Vega

Edmund Ellsworth

Andre S Bachmann

Karsten Melcher

Affiliations

Soon will be listed here.

Abstract

Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC-APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We have revisited the mechanism of APA binding and ODC inhibition through a new crystal structure of APA-bound ODC, which we solved at 2.49 Å resolution. The structure unambiguously shows the presence of a covalent oxime between APA and PLP in the catalytic site, which we confirmed in solution by mass spectrometry. The stable oxime makes extensive interactions with ODC but cannot be catabolized, explaining APA's high potency in ODC inhibition. In addition, we solved an ODC/PLP complex structure with citrate bound at the substrate-binding pocket. These two structures provide new structural scaffolds for developing more efficient pharmaceutical ODC inhibitors.

Citing Articles

Structure simulation-based comparison of active site variations in fungal ornithine decarboxylases.

Kim M, Chang J Commun Integr Biol. 2025; 18(1):2458872.

PMID: 39906711 PMC: 11792860. DOI: 10.1080/19420889.2025.2458872.

Insights into the Functioning of the D-amino Acid Transaminase from Haliscomenobacter Hydrossis via a Structural and Spectral Analysis of its Complex with 3-Aminooxypropionic Acid.

Bakunova A, Matyuta I, Nikolaeva A, Boyko K, Khomutov A, Bezsudnova E Acta Naturae. 2024; 16(3):18-24.

PMID: 39539521 PMC: 11557217. DOI: 10.32607/actanaturae.27496.

DMSO-tolerant ornithine decarboxylase (ODC) tandem assay optimised for high-throughput screening.

Park M, Kim S, Lee C J Enzyme Inhib Med Chem. 2022; 38(1):309-318.

PMID: 36451618 PMC: 9721421. DOI: 10.1080/14756366.2022.2150186.

Structure and Enzymatic Activity of an Intellectual Disability-Associated Ornithine Decarboxylase Variant, G84R.

Zhou X, Schultz C, Suino Powell K, Henrickson A, Lamp J, Brunzelle J ACS Omega. 2022; 7(38):34665-34675.

PMID: 36188294 PMC: 9520691. DOI: 10.1021/acsomega.2c04702.

Biogenic Polyamines and Related Metabolites.

Ivanov A, Khomutov A Biomolecules. 2022; 12(1).

PMID: 35053162 PMC: 8773558. DOI: 10.3390/biom12010014.

References

Almrud J, Oliveira M, Kern A, Grishin N, Phillips M, Hackert M . Crystal structure of human ornithine decarboxylase at 2.1 A resolution: structural insights to antizyme binding. J Mol Biol. 2000; 295(1):7-16. DOI: 10.1006/jmbi.1999.3331. View

Li B, Deng X, Kim S, Buhrow L, Tomchick D, Phillips M . Alternative pathways utilize or circumvent putrescine for biosynthesis of putrescine-containing rhizoferrin. J Biol Chem. 2020; 296:100146. PMC: 7857480. DOI: 10.1074/jbc.RA120.016738. View

Casero Jr R, Marton L . Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov. 2007; 6(5):373-90. DOI: 10.1038/nrd2243. View

Meyskens Jr F, McLaren C, Pelot D, Fujikawa-Brooks S, Carpenter P, Hawk E . Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila). 2008; 1(1):32-8. PMC: 2562024. DOI: 10.1158/1940-6207.CAPR-08-0042. View

Wu D, Kaan H, Zheng X, Tang X, He Y, Vanessa Tan Q . Structural basis of Ornithine Decarboxylase inactivation and accelerated degradation by polyamine sensor Antizyme1. Sci Rep. 2015; 5:14738. PMC: 4595762. DOI: 10.1038/srep14738. View

Heller J, Fong W, Canellakis E . Induction of a protein inhibitor to ornithine decarboxylase by the end products of its reaction. Proc Natl Acad Sci U S A. 1976; 73(6):1858-62. PMC: 430406. DOI: 10.1073/pnas.73.6.1858. View

Battye T, Kontogiannis L, Johnson O, Powell H, Leslie A . iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):271-81. PMC: 3069742. DOI: 10.1107/S0907444910048675. View

Cleveland J . c-myc transactivates the ornithine decarboxylase gene. Curr Top Microbiol Immunol. 1992; 182:445-52. DOI: 10.1007/978-3-642-77633-5_56. View

Milovica V, Turchanowa L, Khomutov A, Khomutov R, Caspary W, Stein J . Hydroxylamine-containing inhibitors of polyamine biosynthesis and impairment of colon cancer cell growth. Biochem Pharmacol. 2001; 61(2):199-206. DOI: 10.1016/s0006-2952(00)00549-9. View

10.

Khomutov A . Inhibition of enzymes of polyamine biosynthesis by substrate-like O-substituted hydroxylamines. Biochemistry (Mosc). 2002; 67(10):1159-67. DOI: 10.1023/a:1020919525067. View

11.

Bassiri H, Benavides A, Haber M, Gilmour S, Norris M, Hogarty M . Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. Transl Pediatr. 2016; 4(3):226-38. PMC: 4729051. DOI: 10.3978/j.issn.2224-4336.2015.04.06. View

12.

Khomutov R, Denisova G, Khomutov A, Belostotskaia K, Shlosman R . [Aminooxypropylamine--an effective inhibitor of ornithine decarboxylase in vitro and in vivo]. Bioorg Khim. 1985; 11(11):1574-6. View

13.

Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U . Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009; 374(9683):56-64. DOI: 10.1016/S0140-6736(09)61117-X. View

14.

Rosenberg-Hasson Y, Strumpf D, Kahana C . Mouse ornithine decarboxylase is phosphorylated by casein kinase-II at a predominant single location (serine 303). Eur J Biochem. 1991; 197(2):419-24. DOI: 10.1111/j.1432-1033.1991.tb15927.x. View

15.

Tang J, Ju Y, Gu Q, Xu J, Zhou H . Structural Insights into Substrate Recognition and Activity Regulation of the Key Decarboxylase SbnH in Staphyloferrin B Biosynthesis. J Mol Biol. 2019; 431(24):4868-4881. DOI: 10.1016/j.jmb.2019.10.009. View

16.

Mett H, Stanek J, Janne J, Alhonen L, Sinervirta R, Frei J . Pharmacological properties of the ornithine decarboxylase inhibitor 3-aminooxy-1-propanamine and several structural analogues. Cancer Chemother Pharmacol. 1993; 32(1):39-45. DOI: 10.1007/BF00685874. View

17.

Packham G, Cleveland J . The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc Natl Acad Sci U S A. 1993; 90(16):7804-8. PMC: 47231. DOI: 10.1073/pnas.90.16.7804. View

18.

Kern A, Oliveira M, Coffino P, Hackert M . Structure of mammalian ornithine decarboxylase at 1.6 A resolution: stereochemical implications of PLP-dependent amino acid decarboxylases. Structure. 1999; 7(5):567-81. DOI: 10.1016/s0969-2126(99)80073-2. View

19.

Klee N, Wong P, Baragana B, El Mazouni F, Phillips M, Barrett M . Selective delivery of 2-hydroxy APA to Trypanosoma brucei using the melamine motif. Bioorg Med Chem Lett. 2010; 20(15):4364-6. PMC: 2935964. DOI: 10.1016/j.bmcl.2010.06.070. View

20.

Jackson L, Brooks H, Osterman A, Goldsmith E, Phillips M . Altering the reaction specificity of eukaryotic ornithine decarboxylase. Biochemistry. 2000; 39(37):11247-57. DOI: 10.1021/bi001209s. View