This is the structure of Sulfide Quinone Oxidoreductase. Structure of Human Sulfide Quinone Oxidoreductase.
This page makes use of Jsmol in Proteopedia [6] and Jmol [7].
Structure
In the PDB, this structure is marked as 6OI5 and is noted as the crystal structure of human sulfide quinone oxidoreductase. This enzyme is comprised of two amino acid chains. It contains a ligand, flavin-adenine dinucleotide (FAD). The FAD is noncovalently bound to the main subunit, and it is in the oxidized state[1]. One residue in this structure was modified into . This modified residue is considered L-type linking and is a potential drug target . In humans, the SQOR is made of two tandem Rossman_fold, and a C-terminal made up of two helices. Rossmann folds are composed of six beta sheets that are arranged parallel to one another with alpha helices connecting the first three strands [1]. The C-terminal extends outward from the main body of the enzyme, and is amphipathic, containing both hydrophobic and hydrophilic portions within the enzyme. The of the protruding C-terminal faces out from the membrane. Following that C-terminal, a penultimate helix arises and is very hydrophobic. It contains 16 hydrophobic residues, 11 of which are facing away from the membrane. The nonpolar residues on this penultimate helix are most tyrosines and methionines, and they face towards a cavity, indicating a binding location for coenzyme Q [1]. Due to the hydrophobic areas making contact to the inner areas of the membrane, the enzyme would be able to make its way towards coenzyme Q and pass off electrons to it. SQOR contains an indent that is electropositive, which will be the location for sulfane sulfur acceptors to bind. Within the middle of the indent, there is an opening just large enough to give access to the one of the reactive cysteine residues. There is a hydrogen sulfide oxidizing site which connects to a hydrophilic pocket, or tunnel, leading to the location where coenzyme Q will eventually bind [1]. Chain A is composed of alpha helices, beta sheets and has numerous binding sites. Chain A also contains many FAD-binding spots. A disulfide bridge connects the positions 161 to 339, or 201 to 379, also denoted by PDB. The spacing between the two cysteine active sites makes strong bridging between the two. The positions of the disulfide bonds are Cys201 and Cys379. Chain B is very much identical to Chain A in that it contains a bridge at the positions Cys201 and Cys379 [2]. Chain B is also made up of alpha helices and beta sheets. It is very much identical to Chain A in that it has a disulfide bridge at the same residues. The resolution of sulfide quinone oxidoreductase is 2.81 angstroms, and the sequence is 418 residues in length. The surface of SQOR that is facing the membrane is characterized by both positive and negative charges [1]. The surface that is facing towards the cellular matrix contains hydrophobic areas, as well as the hydrophobic coenzyme Q binding pocket. The facing the cellular matrix also has a very large positive charge which interacts with the phospholipid bilayer, which is negative. The other side of SQOR contains a large negative surface, where one of the Rossmann folds is located and where the electropositive divet is located [1].
Function
Sulfide quinone oxidoreductase is essential in maintaining sulfide homeostasis, the synthesis of energy through the transfer of electrons, and detoxifying sulfide. Specific functions of SQOR include quinone binding and catalytic activity. Another activity involving SQOR is oxidoreductase functionality. Oxidoreductases can act as either an oxidase or a dehydrogenase (“What are Oxidoreductases?”, 2005). In this enzyme, as stated previously, there are FAD-binding sites, leading to the reduction of FAD+ to FADH2, and dehydrogenases will transfer a hydrogen ion to the accepting FAD+. Besides SQOR there are other examples of oxidoreductases within the body, and they are; peroxidases which are located within peroxisome, waste removing organelles, and hydroxylases, which will add a hydroxyl group to a molecule (see What are Oxidoreductases?). Many cellular components are involved or affected by SQOR including; the cytoplasm and the mitochondrial inner and outer membranes. Oxidoreductases play significant roles in both anaerobic and aerobic metabolism. More specifically, this SQOR enzyme plays a role in mitochondrial metabolism. As previously stated, the main process of SQOR is to metabolize hydrogen sulfide, H2S, but SQOR can also metabolize H2S2 if no sulfane acceptor is present. This SQOR was exposed to a pH of 7, but it can also exist in a more alkaline pH of 8.5 and 7.5. Cyanide appears to be the acceptor when the pH is at 8.5. At the same time, sulfide is the primary acceptor when the pH is at 7. Overall, SQOR functions optimally at physiological pH [8].
Hydrogen Sulfide Metabolism
Hydrogen sulfide metabolism occurs within the mitochondria and consists of about four enzymes. Hydrogen sulfide is flammable, toxic, and has an unpleasant smell. It controls many physiological processes in the cardiovascular, gastrointestinal, and nervous system [2]. The first enzyme involved in the catabolism of hydrogen sulfide is SQOR. The role of SQOR in hydrogen sulfide metabolism is to create thiosulfate by transferring sulfane sulfur atoms from the hydrogen sulfide present [9]. Electrons are transported to the electron transport chain of the mitochondria to reduce coenzyme Q, which occurs in the coenzyme Q binding pocket of SQOR. This is considered a half reaction for both parts because the first part of the reaction is where there is the catabolism of the hydrogen sulfide. The step of this reaction would be the pass off of electrons to coenzyme [2]. Sulfur dioxygenases is the next enzyme that is used to convert GSH persulfide to sulfite. The sulfite produced then gets oxidized by sulfite oxidase to become sulfate. An alternate route to produce thiosulfate would be thiosulfate sulfurtransferase converting sulfide to the desired thiosulfate by adding a persulfide to it [9].
Uses of SQOR
Sulfide quinone oxidoreductase is essential for maintaining healthy levels of hydrogen sulfide within the body. This makes SQOR an attractive drug target. As stated, SQOR can use a multitude of acceptors, also making it open for more diverse ideas in drug design. Hydrogen sulfide’s role within the cardiovascular system indicates SQOR is an important enzyme in increasing or lowering H2S levels. Heart failure has been recently seen to be linked to hydrogen sulfide. With that, pharmaceutical companies are seeing this as a possible point of interest in creating potential cardiovascular drugs. Additionally, hydrogen sulfide aids in post-translational modification [1]. Hydrogen sulfide also regulates ion channels and aids in neuron transmission [9]. Due to its importance in maintaining physiological levels of hydrogen sulfide, SQOR is a possible drug target to decrease cardiovascular and neurological complications and aid in biological processes. Due to hydrogen sulfide being present in the gastrointestinal tract, it is being seen that there is a correlation between levels of hydrogen sulfide and Crohn's disease. It has been seen in Crohn’s patients that there is a substantial amount of hydrogen sulfide and lower amounts of the hydrogen sulfide metabolism enzymes [9]. For this reason SQOR has another reason to become a drug target.
Landmarks on SQOR
The FAD binding site on SQOR is a significant landmark in SQOR. FAD is and is a product of condensation reaction between adenine diphosphate and riboflavin. There are about eleven FAD-binding locations on sulfide quinone oxidoreductase. FAD-binding involves twelve hydrogen bonds to the enzyme, with an addition of interactions with dipoles electrostatically [1]. It is important to note that Lys207 and Lys418 are located near FAD’s binding location, and they are both relatively basic residues. There are also two additional lysine residues at 200 and 344 that are located by the ribityl chain on the FAD [1]. Ribityl chains occur when a terminal hydroxyl group is removed. To help stabilize the charge of the flavin ring, the N-terminus on alpha helix 11 is positioned towards the FAD ring. In addition, alpha helix 1 helps neutralize the charge of the FAD [1]. On the surface of SQOR that is facing the membrane, there is an entrance which leads to the CoQ-binding pocket. Coenzyme Q is very prevalent within cell membranes. This lipid electron transporter, as previously mentioned, is important in SQOR’s pathway to metabolize hydrogen sulfide [1]. Decreased prevalence of coenzyme Q affects the oxidation of hydrogen sulfide, and can cause skin fibroblasts in humans, as recently studied [9].
3D structures of sulfide quinone oxidoreductase
3D structures of sulfide quinone oxidoreductase
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 Jackson MR, Loll PJ, Jorns MS. X-Ray Structure of Human Sulfide:Quinone Oxidoreductase: Insights into the Mechanism of Mitochondrial Hydrogen Sulfide Oxidation. Structure. 2019 Mar 15. pii: S0969-2126(19)30080-2. doi:, 10.1016/j.str.2019.03.002. PMID:30905673 doi:http://dx.doi.org/10.1016/j.str.2019.03.002
- ↑ 2.0 2.1 2.2 2.3 Landry AP, Moon S, Kim H, Yadav PK, Guha A, Cho US, Banerjee R. A Catalytic Trisulfide in Human Sulfide Quinone Oxidoreductase Catalyzes Coenzyme A Persulfide Synthesis and Inhibits Butyrate Oxidation. Cell Chem Biol. 2019 Nov 21;26(11):1515-1525.e4. doi:, 10.1016/j.chembiol.2019.09.010. Epub 2019 Oct 4. PMID:31591036 doi:http://dx.doi.org/10.1016/j.chembiol.2019.09.010
- ↑ 3.0 3.1 Lencina AM, Ding Z, Schurig-Briccio LA, Gennis RB. Characterization of the Type III sulfide:quinone oxidoreductase from Caldivirga maquilingensis and its membrane binding. Biochim Biophys Acta. 2013 Mar;1827(3):266-75. doi: 10.1016/j.bbabio.2012.10.010., Epub 2012 Oct 25. PMID:23103448 doi:http://dx.doi.org/10.1016/j.bbabio.2012.10.010
- ↑ Jackson MR, Melideo SL, Jorns MS. Human sulfide:quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite. Biochemistry. 2012 Aug 28;51(34):6804-15. doi: 10.1021/bi300778t. Epub 2012 Aug, 20. PMID:22852582 doi:http://dx.doi.org/10.1021/bi300778t
- ↑ Toohey JI, Cooper AJ. Thiosulfoxide (sulfane) sulfur: new chemistry and new regulatory roles in biology. Molecules. 2014 Aug 21;19(8):12789-813. doi: 10.3390/molecules190812789. PMID:25153879 doi:http://dx.doi.org/10.3390/molecules190812789
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
- ↑ Jackson MR, Melideo SL, Jorns MS. Human sulfide:quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite. Biochemistry. 2012 Aug 28;51(34):6804-15. doi: 10.1021/bi300778t. Epub 2012 Aug, 20. PMID:22852582 doi:http://dx.doi.org/10.1021/bi300778t
- ↑ 9.0 9.1 9.2 9.3 9.4 Quinzii CM, Luna-Sanchez M, Ziosi M, Hidalgo-Gutierrez A, Kleiner G, Lopez LC. The Role of Sulfide Oxidation Impairment in the Pathogenesis of Primary CoQ Deficiency. Front Physiol. 2017 Jul 25;8:525. doi: 10.3389/fphys.2017.00525. eCollection, 2017. PMID:28790927 doi:http://dx.doi.org/10.3389/fphys.2017.00525
