Typical alkaloids expressed by prokaryotic and eukaryotic cells are small heterocyclic compounds containing weakly basic nitrogen groups that are critically important for mediating essential biological activities. The prototype opiate alkaloid morphine represents a low molecular mass heterocyclic compound that has been evolutionarily fashioned from a relatively restricted role as a secreted antimicrobial phytoalexin into a broad spectrum regulatory molecule. As an essential corollary, positive evolutionary pressure has driven the development of a cognate 6-transmembrane helical (TMH) domain μ3 opiate receptor that is exclusively responsive to morphine and related opiate alkaloids. A key aspect of "morphinergic" signaling mediated by μ3 opiate receptor activation is its functional coupling with regulatory pathways utilizing constitutive nitric oxide (NO) as a signaling molecule. Importantly, tonic and phasic intra-mitochondrial NO production exerts profound inhibitory effects on the rate of electron transport, H+ pumping, and O2 consumption. Given the pluripotent role of NO as a selective, temporally-defined chemical regulator of mitochondrial respiration and cellular bioenergetics, the expansion of prokaryotic denitrification systems into mitochondrial NO/nitrite cycling complexes represents a series of evolutionary modifications of existential proportions. Presently, our short review provides selective discussion of evolutionary development of morphine, opiate alkaloids, μ3 opiate receptors, and NO systems, within the perspectives of enhanced mitochondrial function, cellular bioenergetics, and the human microbiome.

Center for Cognitive and Molecular Neuroscience General University Hospital Prague Prague Czech Republic

Department of Psychiatry 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Senior Advisor International Scientific Information Inc Melville NY USA

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Esch T, Stefano GB. Proinflammation: A common denominator or initiator of different pathophysiological disease processes. Med Sci Monit. 2002;8(5):HY1–9. PubMed

Stefano GB, Scharrer B. Endogenous morphine and related opiates, a new class of chemical messengers. Adv Neuroimmunol. 1994;4:57–68. PubMed

Stefano GB, Goumon Y, Casares F, et al. Endogenous morphine. Trends Neurosci. 2000;9:436–42. PubMed

Stefano GB, Goumon Y, Bilfinger TV, et al. Basal nitric oxide limits immune, nervous and cardiovascular excitation: Human endothelia express a mu opiate receptor. Prog Neurobiol. 2000;60(6):513–30. PubMed

Navarro-Gonzalez R, McKay CP, Mvondo DN. A possible nitrogen crisis for Archaean life due to reduced nitrogen fixation by lightning. Nature. 2001;412(6842):61–64. PubMed

Nna Mvondo D, Navarro-Gonzalez R, McKay CP, et al. Production of nitrogen oxides by lightning and coronae discharges in simulated early Earth, Venus and Mars environments. Adv Space Res. 2001;27(2):217–23. PubMed

Garvin J, Buick R, Anbar AD, et al. Isotopic evidence for an aerobic nitrogen cycle in the latest Archean. Science. 2009;323(5917):1045–48. PubMed

Santana MM, Gonzalez JM, Cruz C. Nitric oxide accumulation: The evolutionary trigger for phytopathogenesis. Front Microbiol. 2017;8:1947. PubMed PMC

Chen J, Strous M. Denitrification and aerobic respiration, hybrid electron transport chains and co-evolution. Biochim Biophys Acta. 2013;1827(2):136–44. PubMed

Wang Y, Ruby EG. The roles of NO in microbial symbioses. Cell Microbiol. 2011;13(4):518–26. PubMed PMC

Tosha T, Shiro Y. Crystal structures of nitric oxide reductases provide key insights into functional conversion of respiratory enzymes. IUBMB Life. 2013;65(3):217–26. PubMed

Ducluzeau AL, van Lis R, Duval S, et al. Was nitric oxide the first deep electron sink? Trends Biochem Sci. 2009;34(1):9–15. PubMed

Gribaldo S, Talla E, Brochier-Armanet C. Evolution of the haem copper oxidases superfamily: A rooting tale. Trends Biochem Sci. 2009;34(8):375–81. PubMed

Crack JC, Munnoch J, Dodd EL, et al. NsrR from Streptomyces coelicolor is a nitric oxide-sensing [4Fe-4S] cluster protein with a specialized regulatory function. J Biol Chem. 2015;290(20):12689–704. PubMed PMC

Serrano PN, Wang H, Crack JC, et al. Nitrosylation of nitric-oxide-sensing regulatory proteins containing [4Fe-4S] clusters gives rise to multiple iron-nitrosyl complexes. Angewandte Chemie. 2016;55(47):14575–79. PubMed PMC

Volbeda A, Dodd EL, Darnault C, et al. Crystal structures of the NO sensor NsrR reveal how its iron-sulfur cluster modulates DNA binding. Nat Commun. 2017;8:15052. PubMed PMC

Socco S, Bovee RC, Palczewski MB, et al. Epigenetics: The third pillar of nitric oxide signaling. Pharmacol Res. 2017;121:52–58. PubMed

Bates TE, Loesch A, Burnstock G, Clark JB. Mitochondrial nitric oxide synthase: A ubiquitous regulator of oxidative phosphorylation? Biochem Biophys Res Commun. 1996;218(1):40–44. PubMed

Brown GC. Nitric oxide and mitochondrial respiration. Biochim Biophys Acta. 1999;1411(2–3):351–69. PubMed

Watt IN, Montgomery MG, Runswick MJ, et al. Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Natl Acad Sci USA. 2010;107(39):16823–27. PubMed PMC

Shen W, Xu X, Ochoa M, et al. Role of nitric oxide in the regulation of oxygen consumption in conscious dogs. Circ Res. 1994;75(6):1086–95. PubMed

Schweizer M, Richter C. Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tension. Biochem Biophys Res Commun. 1994;204(1):169–75. PubMed

Sarti P, Giuffre A, Barone MC, et al. Nitric oxide and cytochrome oxidase: Reaction mechanisms from the enzyme to the cell. Free Radic Biol Med. 2003;34(5):509–20. PubMed

Sarti P, Arese M, Forte E, et al. Mitochondria and nitric oxide: Chemistry and pathophysiology. Adv Exp Med Biol. 2012;942:75–92. PubMed

Sarti P, Forte E, Giuffre A, et al. The chemical interplay between nitric oxide and mitochondrial cytochrome c oxidase: Reactions, effectors and pathophysiology. Int J Cell Biol. 2012;2012:571067. PubMed PMC

Shiva S. Mitochondria as metabolizers and targets of nitrite. Nitric Oxide. 2010;22(2):64–74. PubMed PMC

Stefano GB, Kream RM. Nitric oxide regulation of mitochondrial processes: Commonality in medical disorders. Ann Transplant. 2015;20:402–7. PubMed

Kream RM, Stefano GB. Endogenous morphine and nitric oxide coupled regulation of mitochondrial processes. Med Sci Monit. 2009;15(12):RA263–68. PubMed

Hille R, Nishino T, Bittner F. Molybdenum enzymes in higher organisms. Coord Chem Rev. 2011;255(9–10):1179–205. PubMed PMC

Gray TA, Nicholls RD. Diverse splicing mechanisms fuse the evolutionarily conserved bicistronic MOCS1A and MOCS1B open reading frames. RNA. 2000;6(7):928–36. PubMed PMC

Edwards M, Roeper J, Allgood C, et al. Investigation of molybdenum cofactor deficiency due to MOCS2 deficiency in a newborn baby. Meta Gene. 2015;3:43–49. PubMed PMC

Salloum FN, Sturz GR, Yin C, et al. Beetroot juice reduces infarct size and improves cardiac function following ischemia-reperfusion injury: Possible involvement of endogenous H2S. Exp Biol Med (Maywood) 2015;240(5):669–81. PubMed PMC

Kapil V, Khambata RS, Robertson A, et al. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: A randomized, phase 2, double-blind, placebo-controlled study. Hypertension. 2015;65(2):320–27. PubMed PMC

A report of the Surgeon General: smoking and health. US Government Printing Office; 1979. 1979. Report No.

Stefano GB, Kream RM. Reciprocal regulation of cellular nitric oxide formation by nitric oxide synthase and nitrite reductases. Med Sci Monit. 2011;17(10):RA221–26. PubMed PMC

Brossi A. The alkaloids: Chemistry and pharmacology. New York: Academic Press; 1989.

Begley TP. Encyclopedia of chemical biology. New York: Wiley; 2009.

Fattorusso E, Taglialatela-Scafati O. Modern alkaloids: Structure, isolation, synthesis and biology. New York: Wiley-VCH; 2008.

Aniszewski T. Alkaloids – secrets of life. Amsterdam: Elsevier; 2007.

Kendall MM, Sperandio V. What a dinner party! Mechanisms and functions of interkingdom signaling in host-pathogen associations. MBio. 2016;7(2):e01748. PubMed PMC

Hughes DT, Sperandio V. Inter-kingdom signalling: Communication between bacteria and their hosts. Nat Rev Microbiol. 2008;6(2):111–20. PubMed PMC

Bezanson GS, MacInnis R, Potter G, Hughes T. Presence and potential for horizontal transfer of antibiotic resistance in oxidase-positive bacteria populating raw salad vegetables. Int J Food Microbiol. 2008;127(1–2):37–42. PubMed

Hsiao WW, Metz C, Singh DP, Roth J. The microbes of the intestine: An introduction to their metabolic and signaling capabilities. Endocrinol Metab Clin North Am. 2008;37(4):857–71. PubMed PMC

Liscombe DK, MacLeod BP, Loukanina N, et al. Evidence for the monophyletic evolution of benzylisoquinoline alkaloid biosynthesis in angiosperms. Phytochemistry. 2005;66(11):1374–93. PubMed

Liscombe DK, Facchini PJ. Evolutionary and cellular webs in benzylisoquinoline alkaloid biosynthesis. Curr Opin Biotechnol. 2008;19(2):173–80. PubMed

Kream RM, Stefano GB. De novo biosynthesis of morphine in animal cells: An evidence-based model. Med Sci Monit. 2006;12(10):RA207–19. PubMed

Stefano GB, Ptacek R, Kuzelova H, Kream RM. Endogenous morphine: Up-to-date review 2011. Folia Biol (Praha) 2012;58(2):49–56. PubMed

Simon EJ, Vanpraag D. Inhibition of RNA synthesis in Escherichia Coli by levorphanol. Proc Natl Acad Sci USA. 1964;51:877–83. PubMed PMC

Simon EJ, Vanpraag D. Selective inhibition of synthesis of ribosomal RNA in Escherichia Coli by levorphanol. Proc Natl Acad Sci USA. 1964;51:1151–58. PubMed PMC

Wurster N, Elsbach P, Rand J, Simon EJ. Effects of levorphanol on phospholipid metabolism and composition in Escherichia coli. Biochim Biophys Acta. 1971;248(2):282–92. PubMed

Cabon F, Morser J, Parmantier E, et al. The E. coli envY gene encodes a high affinity opioid binding site. Neurochem Res. 1993;18(7):795–800. PubMed

Persky-Brosh S, Young JR, Holland MJ, Simon EJ. Effect of morphine analogues on chemotaxis in Escherichia coli. J Gen Microbiol. 1978;107(1):53–58. PubMed

Cadet P, Mantione KJ, Zhu W, et al. A functionally coupled mu3-like opiate receptor/nitric oxide regulatory pathway in human multi-lineage progenitor cells. J Immunol. 2007;179(9):5839–44. PubMed

Kream RM, Sheehan M, Cadet P, et al. Persistence of evolutionary memory: Primordial six-transmembrane helical domain mu opiate receptors selectively linked to endogenous morphine signaling. Med Sci Monit. 2007;13(12):SC5–6. PubMed

Radomski MW, Palmer RMJ, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the consitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci USA. 1990;87:10043–47. PubMed PMC

Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43(2):109–42. PubMed

Moncada S, Palmer RM, Higgs EA. The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension. 1988;12:365–72. PubMed

Moncada S, Palmer RM, Higgs EA. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol. 1989;38(11):1709–15. PubMed

Ignarro LJ, Lippton H, Edwards JC, et al. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther. 1981;218(3):739–49. PubMed

Ignarro LJ. Signal transduction mechanisms involving nitric oxide. Biochem Pharmacol. 1991;41(4):485–90. PubMed

Griscavage JM, Rogers NE, Sherman MP, Ignarro LJ. Inducible nitric oxide synthase from a rat alveolar macrophage cell line is inhibited by nitric oxide. J Immunol. 1993;151(11):6329–37. PubMed

Mastronicola D, Arcuri E, Arese M, et al. Morphine but not fentanyl and methadone affects mitochondrial membrane potential by inducing nitric oxide release in glioma cells. Cell MolLife Sci. 2004;61(23):2991–97. PubMed

di Jeso F, Giorgini D, Truscello A. [In vitro effect of morphine on oxidative phosphorylation in mitochondria on non-neural cells]. CR Seances Soc Biol Fil. 1982;176(2):151–53. [in French] PubMed

di Jeso B, Truscello A, di Jeso F. [Morphine receptors in rat liver mitochondrial membranes]. CR Seances Soc Biol Fil. 1984;178(1):52–55. [in French] PubMed

Stefano GB, Mantione KJ, Capellan L, et al. Morphine stimulates nitric oxide release in human mitochondria. J Bioenerg Biomembr. 2015;47(5):409–17. PubMed

Stefano GB, Kream RM. Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review) Int J Mol Med. 2016;37:547–55. PubMed PMC

Stefano GB, Ptacek R, Raboch J, Kream RM. Microbiome: A potential component in the origin of mental disorders. Med Sci Monit. 2017;23:3039–43. PubMed PMC

Stefano GB, Zhu W, Cadet P, Mantione K. Morphine enhances nitric oxide release in the mammalian gastrointestinal tract via the m3 opiate receptor subtype: A hormonal role for endogenous morphine. J Physiol Pharmacol. 2004;55(1 Pt 2):279–88. PubMed

Dowd SE. Escherichia coli O157: H7 gene expression in the presence of catecholamine norepinephrine. FEMS Microbiol Lett. 2007;273(2):214–23. PubMed

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