Dalton Transactions Blog

Enzymes function as biological catalysts in a wide array of reactions which are essential for sustaining life. They are almost always large protein molecules which adopt complex three dimensional structures, yet are able to remain structurally dynamic in order to allow the function of the enzyme to be switched on and off.

This feature allows an enzyme’s catalytic activity to be active only when required in the metabolic pathway in which it is involved. For this reason, enzymes have long been a source of inspiration to researchers involved in the design and synthesis of artificial molecular switches and machines.

SARS-CoV 3CLpro is a protease enzyme which is involved in the replication and transcription process of the human coronavirus, the virus which causes severe acute respiratory syndrome (SARS). This enzyme is catalytically inactive as a monomer and only functions as a catalyst when it is bound with another monomer in a complex called a homodimer.

Both crystallographic and mutation studies have implicated several amino acid residues in the dimerization process, however the exact mechanism of dimer formation and how this activates the enzyme’s catalytic activity is still unconfirmed.

 Scheme 1. Switching between open and close conformations of nanoswitch 1 in response to metal ion addition

Drawing inspiration from this monomer-dimer on-off mechanism, Schmittel and co-workers have devised a molecular switch capable of toggling between monomeric and dimeric forms in response to the addition of different metal ions. With no metal ions present, the triangular framework adopts the ‘OPEN-I’ conformation (Scheme 1). Upon the addition of copper(I) ions, the two pyridine-based ligands come into proximity to mutually coordinate the metal.

This changes the conformation of the framework to the ‘CLOSE’ state. Addition of iron(II) ions to the ‘CLOSE’ state again changes the molecular conformation, as the iron(II) ions occupy the terpyridine moiety and the copper(I) ions move to occupy only the shielded phenanthroline ligand.

This both forms a homoleptic dimer, as the iron(II) ions can coordinate two terpyridine moieties simultaneously from two different molecules, and creates a coordinatively unsaturated copper species which acts as a catalyst for a cyclopropanation reaction. The authors impressively demonstrate the reversibility of each step, with the removal of metal ions changing the framework back to its uncoordinated conformation.

In this way, they have successfully made a molecular switch which responds to a metal ion signal (Fe²⁺) and turns a catalytic complex on and off. Like SARS-CoV 3CLpro enzyme, the catalytically active state is the homodimer, with the monomeric form being catalytically inactive.

To find out more, read the full article:

A monomer-dimer nanoswitch that mimics the working principle of the SARS-CoV 3CLpro enzyme controls copper-catalysed cyclopropanation
Soumen De, Susnata Pramanik and Michael Schmittle
Dalton Trans. 2014, DOI:10.1039/c4dt01508h

Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.

Hypochlorous acid (HOCl) is a weak acid, formed from the reaction of chlorine with water. In addition to its use as a reagent in organic chemistry, it has significant biological relevance. HOCl is generated in biological systems in a reaction between chloride ions and hydrogen peroxide, catalysed by the enzyme myeloperoxidase.

This enzyme is secreted by phagocytes (cells which help protect the body by ‘ingesting’ bacteria) when they are activated during an immune response. Hypochlorite (ClO^–), the conjugate base of HOCl, is extremely toxic to bacteria and plays a vital role in assisting the activated phagocytes with killing a wide range of pathogens.¹

Excess production of HOCl in a living system can have a detrimental effect, as HOCl can react with many different biological molecules, including DNA, cholesterol and proteins, leading to changes in their biological properties. An example of this is the reaction of hypochlorous acid with unsaturated bonds in lipids, which produces a species called a chlorohydrin. This disrupts the formation of the essential lipid by-layers which form around cells.

Excess hypochlorous acid has been implicated in conditions such as inflammatory diseases, neurodegeneration and cancers.² In order to fully understand the role of HOCl in these biological processes, accurate detection methods must be developed to monitor the molecule in living cells.

Several ‘HOCl-recognising’ molecules have been found to be effective sensors of hypochlorous acid. When conjugated with a fluorophore, these probes can successfully ‘recognise’ HOCl by reacting with it, however their application in vivo is still limited due to their excitation wavelengths being in the ultraviolet region of light.³ Sensors with adsorption (or emission) in the visible light range are more desirable for clinical diagnostic applications. 

In one recent paper in Dalton Transactions, Yuan and co-workers combine an excellent HOCl-recognising moiety: 4-amino-3-nitrol phenol) and a ruthenium(II)-2,2-bipyridyl complex, which is well known to exhibit visible light adsorption and emission, into one compound to create a luminescent probe for HOCl.

The resulting complex [Ru(bpy)₂(AN-bpy)][PF₆]₂ is very weakly luminescent but, upon reaction with HOCl in aqueous media, converts to [Ru(bpy)₂(HM-bpy)][PF₆]₂, which has a luminescence signal which is 110-fold stronger.

Impressively, the authors show that when HeLa cells are incubated with [Ru(bpy)₂(AN-bpy)][PF₆]₂ for two hours they remain non-luminescent; when the same cells are subsequently treated with HOCl for thirty minutes, a bright red luminescence is observed, clearly demonstrating the potential for using this ruthenium complex as an in vivo, luminescent detector of hypochlorous acid. 

To find out more, read the article using the link below:

Development of a functional ruthenium(II) complex for probing hypochlorous acid in living cells
Dalton Trans. 2014, DOI:10.1039/C4DT00179F

Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.

References  

 ¹ J. M. Albrich, C. A. McCarthy, J. K. Hurst, Prot. Nat. Acad. Sci., 1981, 78, 210.
²  T. I. Kim, S. Park, Y. Choi, Y. Kim, Chem.-Asian J., 2011, 6, 1358
³ Y. Xiao, R. Zhang, Z. Ye, Z. Dai, H. An, J. Yuan, Anal. Chem., 2012, 84, 10785.

Direct capture of CO₂ from the air presents significant challenges, one of which is the separation of CO₂ from other gases. Currently, a lot of waste carbon dioxide is captured at the emission source – fossil fuel-powered energy plants – by a ‘filter’ that traps the CO₂ as it travels up a chimney. This method can prevent up to 90% of a power plant’s carbon emissions from entering the atmosphere, however the process requires a lot of energy and the captured gas still needs to be transported to a suitable storage area. New technologies for selective capture of carbon dioxide from the air are still in their infancy, but could offer more efficient ways to trap CO₂ anywhere on the planet, not just at the sources of emission. 

Figure 1: Double chain MOF

Metal organic frameworks (MOFs), also known as coordination polymers, are compounds containing metal ions which are coordinated to organic molecules to form extensive two- or three-dimensional structures. The uniform and controllable porosity of these materials has already been exploited as potential devices for gas capture and storage.² In one recent paper in Dalton Transactions, Kim and co-workers synthesise novel MOFs using cobalt and zinc metal ions coordinated to porphyrin-based molecules. The resulting MOFs display an interesting 1D ‘double chain’ arrangement of molecules (Figure 1). These ‘double chains’ pack together tightly, forming hydrogen bonds between the ‘chains’, resulting in a stable solid state structure with defined pores. Gas sorption experiments revealed that these new MOFs both show high uptake of CO₂ gas compared with nitrogen (N₂), hydrogen (H₂) and methane (CH₄), (Figure 2), making these types of materials excellent candidates for selective CO₂ capture from the air. 

Figure 2: Gas uptake by double-chain MOF

Find out more and download the article now:
CO₂ selective 1D double chain dipyridyl-porphyrin based porous coordination polymers 
Dalton Trans. 2014, DOI:10.1039/C3DT53287A 

References 

¹ IPCC Special Report, ‘Carbon Dioxide Capture and Storage’, IPCC Working Group III, 2005. 
² S. L. James, Chem. Soc. Rev., 2003, 32, 276.

Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.

Bacterial resistance to standard types of antibiotics is a growing problem in medical science. The most famous example is MRSA, which stands for Methicillin-resistant Staphylococcus aureus. This name refers to a bacterium which, through the process of natural selection, is now resistant to a class of antibiotics called beta-lactams (which include penicillin and the cephalosporins). MRSA is especially dangerous in environments like hospitals and nursing homes, where patients or residents with weakened immune systems are at greater risk of infection (compared with the general public). The Office for National Statistics reports that between 1993 and 2005, the number of deaths associated with MRSA rose from 51 to 1,652.¹

Methods to try and fight this growing threat include increased sanitization of areas where people are most at risk of infection and screening patients for the bacteria upon hospital admission and separating carriers from non-carriers. In the scientific community, development of new compounds which are capable of killing MRSA and other antibiotic resistant bacteria is a highly important, ongoing research area.²

Metal complexes displaying biological activity have been widely reported; in particular complexes containing the metal ruthenium have been shown to display anti-cancer, anti-microbial and DNA binding abilities.³ In this paper, the authors synthesise several new ruthenium complexes and perform tests to assess their anti-microbial activity against MRSA.

Structure of ruthenium complexes synthesized

A ‘zone of clearance’ study pitted two of the new ruthenium complexes against methicillin in a test of how effectively each compound inhibited bacterial growth (see below). The ruthenium complexes were shown to have superior anti-MRSA activity when compared with methicillin, suggesting they could provide prolonged antibacterial activity when used as topical antibiotics.

‘Zone of clearance’ assay results

To read more, download the article now:
“Development of ruthenium(II) complexes as topical antibiotics against methicillin resistant Staphylococcus aureus”
W.-Y. Wong et al., Dalton Trans. 2014, DOI:10.1039/C3DT52879K

References:

¹ UK Office for National Statistics, www.ons.gov.uk
² P. A. Ashford, S. P. Bew, Chem. Soc. Rev., 2012, 41, 957
³ C. S. Allardyce, P. J. Dyson, Platinum Metals Rev., 2001, 45, 62

Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.