The Substrate-free and -bound Crystal Structures of the Duplicated Taurocyamine Kinase from the Human Parasite Schistosoma mansoni

Abstract

Background: Trematode taurocyamine kinases are contiguous dimers of unknown structure. Results: The first reported crystal structure of taurocyamine kinase displays an original bilobal arrangement compared with true dimeric phosphagen kinases. Conclusion: Each lobe is capable of enzymatic activity and substrate binding in a non-mutually exclusive manner. Significance: This structure can serve as a tool for the rational design of anti-schistosomiasis drugs.

Natural Products Containing ‘Rare’ Organophosphorus Functional Groups

“…Phosphagen kinases are enzymes that catalyze the reversible Mg 2+ -dependent transfer of the gamma phosphoryl group of ATP to a naturally occurring guanidino compounds, proto-phosphagens, such as creatine, glycocyamine, taurocyamine, lombricine, and arginine. Phosphagen kinases are a highly conserved family of proteins that nevertheless differ significantly with respect to their enzyme specificity and protein structure (monomeric, dimeric, and oligomeric forms of phophagen kinases are known) and distribution in the cell [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Among the most studied phosphagen kinases is the creatine kinase (EC 2.7.3.2), which is the only known phosphagen kinase to exist in vertebrates [ 71 , 72 , 73 , 74 ].…”

“…It is still debated if bacterial arginine kinases identified in those few species are evidence of ancient evolutionary history of N -phosphoarginine and phosphoramidates or have been acquired by horizontal gene transfer from eukaryotes [ 53 , 54 , 55 ]. Other, less studied phosphagen kinases that were identified in invertebrates include hypotaurocyamine kinase (EC 2.7.3.6) [ 77 ], so far identified only in peanut worms [ 78 ], glycocyamine kinase (EC 2.7.3.1), lombricine and thalessemine kinases (EC 2.7.3.5), opheline kinase (EC 2.7.3.7), and taurocyamine kinase (EC 2.7.3.4) [ 51 , 79 , 80 ], identified mostly in annelids with several potential examples identified in trematodes [ 59 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ] and unicellular oomycetes [ 51 , 79 , 80 ]. One phosphagen kinase, agmatine kinase (EC 2.7.3.10), appears to be specific only to protozoa [ 90 ] ( Table 1 ).…”

“…It is suggested that this unusual phosphagen system evolved from molluscan N -phosphoarginine kinase [ 78 ]. N -phosphotaurocyamine ( 21 ) is a sulfonic acid phosphagen synthesized by a widespread taurocyamine kinase (EC 2.7.3.4) identified in a large number of annelid species [ 59 , 81 , 82 , 83 , 84 , 85 ]. However, recent identification of taurocyamine kinases in a large number of non-annelid species, including trematodes Paragonimus westermani , Schistosoma japonicum , Clonorchis sinensis [ 82 , 83 , 86 , 87 , 88 , 89 ] and, in two isolated cases in unicellular oomycetes [ 82 , 83 , 86 , 87 , 88 , 89 ], suggests that the evolutionary and phylogenetic scope of alternative substrate specificities of phosphagen kinases may be more widespread than previously thought [ 105 ].…”

Elevated μs-ms timescale backbone dynamics in the transition state analog form of arginine kinase

“…In the 1.2 Å resolution crystal structure of the arginine kinase TSA complex, neither the substrate arginine, ADP, nor the nitrate ion are constrained covalently , yet the nitrate ion is observed in almost the exact position the phosphoryl group would be expected to be in the actual transition state with partial covalent bonding to both nucleotide β-phosphate and arginine guanidinium (Yousef et al, 2002; Zhou et al, 1998). Analogous complexes have been used to solve TSA crystal structures of other phosphagen kinases: glycocyamine kinase, taurocyamine kinase, and creatine kinase (Lahiri et al, 2002; Lim et al, 2010; Merceron et al, 2015). …”