A bioinformatics view of zinc enzymes

Abstract

Thanks to the contributions of scientists like Bert Vallee, zinc enzymology is an area of research with a rich history and a strong basis of biochemical and biophysical knowledge. In recent years, the dramatic development of the genomic and post-genomic research has provided this as well as all other fields of life sciences with a massive body of new data, including, but not limited to, protein sequence and structural data. By integrating these new data with the wealth of information available in the literature, it is possible to achieve an unprecedented overview of the properties and functions of zinc enzymes in the context of biological systems. To this aim, the role of bioinformatics is essential. In this work, we use bioinformatics tools and databases that we have developed for the study of metalloproteins to gain insights into the functions of zinc in zinc enzymes, its coordination properties, and the usage of zinc enzymes in living organisms.

Introduction

Zinc is an essential element for all forms of life. The first demonstration that zinc is indispensable to living organisms dates back to 1869, when Raulin showed that it is required for the growth of Aspergillus niger, a filamentous fungus [1]. However, a specific biological function for zinc was first established only in 1940, when it was shown to be a necessary catalytic cofactor of carbonic anhydrase [2]. Since then, zinc has been found to be associated with an impressive variety of proteins responsible for a wide range of physiological activities, thereby explaining its involvement in many different biological processes such as protein synthesis and degradation, DNA metabolism and repair, and neurotransmission [3], [4]. In particular, a vast wealth of information on zinc enzymes, including data on three-dimensional structures, kinetic and biochemical properties, and reaction mechanisms, has been accumulated over the years, and Bert Vallee has been an unquestioned leader in laying the foundation and building the body of knowledge of zinc enzymology [5], [6], [7], [8], [9], [10], [11], [12].

In the last 10–15 years of his life, Bert Vallee was a witness of the revolutionary changes undergone by biological sciences as a result of the advent of genome sequencing and post-genomic projects. The progress of high-throughput technologies capable of providing omics-type data (e.g., genomics, proteomics) opened the possibility of having virtually complete lists of the molecular components of cells, leading to the renewal of efforts aimed at understanding living organisms at the systems level [13], [14]. In parallel, the number of atomic resolution structures solved was boosted by the numerous structural genomics projects pursuing the determination of protein structures on a genome-wide scale [15]. A fruitful use of these unprecedented amounts of data strongly relies on the development of bioinformatics approaches, which are essential to store, analyze and interpret the experimental results [16], [17]. Examining the diverse data available through the lens of bioinformatics offers researchers a bird's eye view of the molecular mechanisms underlying biological processes, which represents a crucial change of perspective with respect to the classical reductionist approach of investigating individual molecules one by one.

In this work, we illustrate with some examples how bioinformatics resources, including tools and databases developed by ourselves, can be used to achieve a functional overview of the subject of most of Bert Vallee's research, i.e., zinc enzymes. We show that computational analysis can derive useful insights and principles from the structural and functional data on zinc enzymes collected by Bert Vallee and many other scientists, without whose contributions there would simply be nothing to make sense of.