Highlighting Human Enzymes Active in Different Metabolic Pathways and Diseases: The Case Study of EC 1.2.3.1 and EC 2.3.1.9

Abstract

Enzymes are key proteins performing the basic functional activities in cells. In humans, enzymes can be also responsible for diseases, and the molecular mechanisms underlying the genotype to phenotype relationship are under investigation for diagnosis and medical care. Here, we focus on highlighting enzymes that are active in different metabolic pathways and become relevant hubs in protein interaction networks. We perform a statistics to derive our present knowledge on human metabolic pathways (the Kyoto Encyclopaedia of Genes and Genomes (KEGG)), and we found that activity aldehyde dehydrogenase (NAD(+)), described by Enzyme Commission number EC 1.2.1.3, and activity acetyl-CoA C-acetyltransferase (EC 2.3.1.9) are the ones most frequently involved. By associating functional activities (EC numbers) to enzyme proteins, we found the proteins most frequently involved in metabolic pathways. With our analysis, we found that these proteins are endowed with the highest numbers of interaction partners when compared to all the enzymes in the pathways and with the highest numbers of predicted interaction sites. As specific enzyme protein test cases, we focus on Alpha-Aminoadipic Semialdehyde Dehydrogenase (ALDH7A1, EC 2.3.1.9) and Acetyl-CoA acetyltransferase, cytosolic and mitochondrial (gene products of ACAT2 and ACAT1, respectively; EC 2.3.1.9). With computational approaches we show that it is possible, by starting from the enzyme structure, to highlight clues of their multiple roles in different pathways and of putative mechanisms promoting the association of genes to disease.

Accelerating Biocatalysis Discovery with Machine Learning: A Paradigm Shift in Enzyme Engineering, Discovery, and Design

“…A further example is the appearance of a new enzyme function in the study of disease mechanisms, where the known involvement of a particular protein in causing the disease is suddenly explained by discovering the underlying enzymatic activity. This kind of discovery may appear arbitrary at first, but is made very plausible if not likely in the light of the extensive network of human enzymes and the way their activity is interlinked across multiple different metabolic pathways and diseases …”

“…This kind of discovery may appear arbitrary at first, but is made very plausible if not likely in the light of the extensive network of human enzymes and the way their activity is interlinked across multiple different metabolic pathways and diseases. 52 In summary, enzyme discovery is overshadowed by enzyme engineering in the literature and certainly in practice but must not be neglected due to its potential for exciting new functionality that is waiting to be discovered.…”

“…This kind of discovery may appear arbitrary at first, but is made very plausible if not likely in the light of the extensive network of human enzymes and the way their activity is interlinked across multiple different metabolic pathways and diseases. 52 …”

Ribosomal protein dynamics and plasticity in the cell body and processes of neurons

“…Intriguingly, I and others have observed mRNAs encoding for core ribosomal proteins (RPs) among the genes most enriched in neuronal processes. This observation challenges two historical assumptions of ribosome biology: (1) new RPs are incorporated only into newly forming ribosomes, and (2) this incorporation occurs only in the nucleus and perinuclear region. In my PhD, I aimed to directly test these two assumptions and if proven wrong ask whether and why neurons would localize RP mRNAs far from their known assembly site.…”

“…As discussed in paragraph 2.4.1, increased sensitivity and statistical power would allow for a more accurate assessment of the subtle differences in RP stoichiometry indicated by the simple t-test (Figure2. 7c).Additionally, better resolved biological samples (for example, based on translational state or subcellular location) could reveal potential specializations.The discrepancy between differential abundance of RPs observed at the mRNAs and proteins levels in total lysates but not in fractions enriched for assembled ribosomes, could be reconciled by three non-mutually exclusive mechanisms:(1) biological stochasticity which is corrected for at the post-transcriptional and posttranslational level, (2) extra-ribosomal functions of non-assembled RPs, (3) contextdependent regulation of RP incorporation into assembled ribosomes. Indeed, our analysis revealed a significant difference in the relative amounts of several RPs between the samples which include both free and assembled proteins, and samples in which only assembled ribosomes were quantified (Figure2.…”