The Enzymatic Function of the Honorary Enzyme: S-nitrosylation of Hemoglobin in Physiology and Medicine

Overview

Journal Mol Aspects Med

Specialties Biochemistry
Molecular Biology

Date 2021 Dec 2

PMID 34852941

Citations 7

Authors

Richard T Premont

David J Singel

Jonathan S Stamler

Affiliations

Soon will be listed here.

Abstract

The allosteric transition within tetrameric hemoglobin (Hb) that allows both full binding to four oxygen molecules in the lung and full release of four oxygens in hypoxic tissues would earn Hb the moniker of 'honorary enzyme'. However, the allosteric model for oxygen binding in hemoglobin overlooked the essential role of blood flow in tissue oxygenation that is essential for life (aka autoregulation of blood flow). That is, blood flow, not oxygen content of blood, is the principal determinant of oxygen delivery under most conditions. With the discovery that hemoglobin carries a third biologic gas, nitric oxide (NO) in the form of S-nitrosothiol (SNO) at β-globin Cys93 (βCys93), and that formation and export of SNO to dilate blood vessels are linked to hemoglobin allostery through enzymatic activity, this title is honorary no more. This chapter reviews evidence that hemoglobin formation and release of SNO is a critical mediator of hypoxic autoregulation of blood flow in tissues leading to oxygen delivery, considers the physiological implications of a 3-gas respiratory cycle (O/NO/CO) and the pathophysiological consequences of its dysfunction. Opportunities for therapeutic intervention to optimize oxygen delivery at the level of tissue blood flow are highlighted.

Citing Articles

Regulation of nitric oxide generation and consumption.

Abu-Soud H, Camp O, Ramadoss J, Chatzicharalampous C, Kofinas G, Kofinas J Int J Biol Sci. 2025; 21(3):1097-1109.

PMID: 39897032 PMC: 11781162. DOI: 10.7150/ijbs.105016.

Relationships between Iron Status and Selected Physical Fitness Components of South African Adolescents: The PAHL-Study.

Monyeki M, Veldsman T, Coetzee B, Sparks M, Moss S, Pienaar C Children (Basel). 2024; 11(6).

PMID: 38929238 PMC: 11202035. DOI: 10.3390/children11060659.

Smart Magnetic Nanocarriers for Codelivery of Nitric Oxide and Doxorubicin for Enhanced Apoptosis in Cancer Cells.

Dutta B, Shelar S, Nirmalraj A, Gupta S, Barick K, Gupta J ACS Omega. 2023; 8(47):44545-44557.

PMID: 38046289 PMC: 10688159. DOI: 10.1021/acsomega.3c03734.

Research on the Current Application Status of Magnesium Metal Stents in Human Luminal Cavities.

Chen X, Xia Y, Shen S, Wang C, Zan R, Yu H J Funct Biomater. 2023; 14(9).

PMID: 37754876 PMC: 10532415. DOI: 10.3390/jfb14090462.

Hemoglobin and cerebral hypoxic vasodilation in humans: Evidence for nitric oxide-dependent and -nitrosothiol mediated signal transduction.

Hoiland R, MacLeod D, Stacey B, Caldwell H, Howe C, Nowak-Fluck D J Cereb Blood Flow Metab. 2023; 43(9):1519-1531.

PMID: 37042194 PMC: 10414015. DOI: 10.1177/0271678X231169579.

References

Hess J . Red cell changes during storage. Transfus Apher Sci. 2010; 43(1):51-9. DOI: 10.1016/j.transci.2010.05.009. View

Olson J, Mathews A, Rohlfs R, Springer B, Egeberg K, Sligar S . The role of the distal histidine in myoglobin and haemoglobin. Nature. 1988; 336(6196):265-6. DOI: 10.1038/336265a0. View

Stamler J, Simon D, Osborne J, Mullins M, Jaraki O, Michel T . S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci U S A. 1992; 89(1):444-8. PMC: 48254. DOI: 10.1073/pnas.89.1.444. View

Matto F, Kouretas P, Smith R, Ostrowsky J, Cina A, Hess D . S-Nitrosohemoglobin Levels and Patient Outcome After Transfusion During Pediatric Bypass Surgery. Clin Transl Sci. 2017; 11(2):237-243. PMC: 5867013. DOI: 10.1111/cts.12530. View

McMahon T, Moon R, Luschinger B, Carraway M, Stone A, Stolp B . Nitric oxide in the human respiratory cycle. Nat Med. 2002; 8(7):711-7. DOI: 10.1038/nm718. View

Perutz M . Mechanisms regulating the reactions of human hemoglobin with oxygen and carbon monoxide. Annu Rev Physiol. 1990; 52:1-25. DOI: 10.1146/annurev.ph.52.030190.000245. View

Bennett-Guerrero E, Veldman T, Doctor A, Telen M, Ortel T, Reid T . Evolution of adverse changes in stored RBCs. Proc Natl Acad Sci U S A. 2007; 104(43):17063-8. PMC: 2040393. DOI: 10.1073/pnas.0708160104. View

Stamler J, Jia L, Eu J, McMahon T, Demchenko I, Bonaventura J . Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science. 1997; 276(5321):2034-7. DOI: 10.1126/science.276.5321.2034. View

Ross J, FAIRCHILD H, WELDY J, GUYTON A . Autoregulation of blood flow by oxygen lack. Am J Physiol. 1962; 202:21-4. DOI: 10.1152/ajplegacy.1962.202.1.21. View

10.

Nagababu E, Ramasamy S, Rifkind J . S-nitrosohemoglobin: a mechanism for its formation in conjunction with nitrite reduction by deoxyhemoglobin. Nitric Oxide. 2006; 15(1):20-9. DOI: 10.1016/j.niox.2006.01.012. View

11.

Cortese-Krott M, Kelm M . Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function?. Redox Biol. 2014; 2:251-8. PMC: 3909820. DOI: 10.1016/j.redox.2013.12.027. View

12.

Castillo L, Beaumier L, Ajami A, Young V . Whole body nitric oxide synthesis in healthy men determined from [15N] arginine-to-[15N]citrulline labeling. Proc Natl Acad Sci U S A. 1996; 93(21):11460-5. PMC: 38079. DOI: 10.1073/pnas.93.21.11460. View

13.

Beall C . Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci U S A. 2007; 104 Suppl 1:8655-60. PMC: 1876443. DOI: 10.1073/pnas.0701985104. View

14.

CHANUTIN A, CURNISH R . Effect of organic and inorganic phosphates on the oxygen equilibrium of human erythrocytes. Arch Biochem Biophys. 1967; 121(1):96-102. DOI: 10.1016/0003-9861(67)90013-6. View

15.

Hogg N . The biochemistry and physiology of S-nitrosothiols. Annu Rev Pharmacol Toxicol. 2002; 42:585-600. DOI: 10.1146/annurev.pharmtox.42.092501.104328. View

16.

Pawloski J, Hess D, Stamler J . Export by red blood cells of nitric oxide bioactivity. Nature. 2001; 409(6820):622-6. DOI: 10.1038/35054560. View

17.

Mahecic T, Dunser M, Meier J . RBC Transfusion Triggers: Is There Anything New?. Transfus Med Hemother. 2020; 47(5):361-368. PMC: 7590774. DOI: 10.1159/000511229. View

18.

Weinberg J, Maclennan P, Vandromme-Cusick M, Magnotti L, Kerby J, Rue 3rd L . The deleterious effect of red blood cell storage on microvascular response to transfusion. J Trauma Acute Care Surg. 2013; 75(5):807-12. PMC: 3831610. DOI: 10.1097/TA.0b013e3182a74a9b. View

19.

Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-10. PMC: 4968574. DOI: 10.1001/jama.2016.0287. View

20.

Douglas C, Haldane J, Haldane J . The laws of combination of haemoglobin with carbon monoxide and oxygen. J Physiol. 1912; 44(4):275-304. PMC: 1512793. DOI: 10.1113/jphysiol.1912.sp001517. View