Back to the Future of Metabolism-Advances in the Discovery and Characterization of Unknown Biocatalytic Functions and Pathways

Abstract

The architecture, organization, and functioning of biocatalytic reaction networks, which are coded in the cell-specific genome and which work together in the small space of biological cells, are a fascinating feature of life evolved over more than 3 billion years. Knowledge about the diversity of biocatalytic functions and metabolic pathways sustaining life on our planet is highly important, especially as the currently occurring loss of biodiversity is considered a planetary boundary that is at high risk, and knowledge about the life of current biological organisms should be gained before they become extinct. In addition to the well-known enzymatic reactions involved in biochemical pathways, the enzyme universe offers numerous opportunities for discovering novel functions and pathways. Maintaining thousands of molecules and reactions functioning properly within biological cells, which may be exposed to various kinds of external hazards, environmental stress, enzymatic side reactions, or non-enzymatic chemical reactions, is key for keeping cellular life healthy. This review aims to outline advances in assigning enzyme functions to protein sequences and the discovery of novel biocatalytic functions and pathways.

Keywords: biosynthesis; biosynthetic gene clusters; central metabolic pathways; cryptic pathways; domains of unknown functions; enzyme functions; metabolite repair enzymes; orphan pathways; silent pathways.

Figure 1

Assignment and characterization of enzyme functions for selected DUF proteins.

Figure 2

Identification of a missing enzymatic reaction step in the biosynthesis of altemicidin.

Figure 3

Proposed unifying pathway in the deciphering of the biosynthesis of the enediyne aromatic polyketides.

Figure 4

Diverse natural and synthetic salvage pathways that have been discovered, proposed, and designed for S-adenosyl-L-homocysteine, L-methionine, 5′-methylthioadenosine, and 5′-deoxy-adenosine.

Figure 5

Discovery of the metabolite repair enzyme L-glyceraldehyde-3-phosphate reductase catalyzing the stereospecific, NADPH-dependent reduction of L-glyceraldehyde-3-phosphate to the non-toxic natural metabolite L-glycerol-3-phosphate (sn-glycerol-3-phosphate).