Location, location! cellular relocalization primes specialized metabolic diversification

Abstract

Specialized metabolites are structurally diverse and cell‐ or tissue‐specific molecules produced in restricted plant lineages. In contrast, primary metabolic pathways are highly conserved in plants and produce metabolites essential for all of life, such as amino acids and nucleotides. Substrate promiscuity – the capacity to accept non‐native substrates – is a common characteristic of enzymes, and its impact is especially apparent in generating specialized metabolite variation. However, promiscuity only leads to metabolic diversity when alternative substrates are available; thus, enzyme cellular and subcellular localization directly influence chemical phenotypes. We review a variety of mechanisms that modulate substrate availability for promiscuous plant enzymes. We focus on examples where evolution led to modification of the ‘cellular context’ through changes in cell‐type expression, subcellular relocalization, pathway sequestration, and cellular mixing via tissue damage. These varied mechanisms contributed to the emergence of structurally diverse plant specialized metabolites and inform future metabolic engineering approaches.

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

“…For instance, the disturbances in metabolites of the glycolytic pathway (glucose-6-phosphate and glycerol-3-phosphate) and tricarboxylic acid (TCA) cycle (α-ketoglutarate, fumarate, and succinate) were identified in astrocytes derived from newborn 5xFAD mice [11], and pantethine treatment reduced the extent of metabolic perturbation and decreased the inflammatory processes in these astrocytes, indicating the role of altered brain energetics in the AD pathogenesis; metabolic profile analyses revealed region-specific metabolic changes in the hippocampus, cortex, cerebellum, and olfactory bulbs in APP/PS1 mice [12,13], and metabolomics signatures, including mitochondrial dysfunction and altered energy metabolism indicated by changes in nucleotide, TCA cycle, energy transfer, neurotransmitter, and amino acid metabolic pathways, were identified in APP/PS1 mice [14]; in addition, significant changes in metabolite compositions, including accumulation of fatty acids, alterations in phospholipids and acylcarnitines related to neural membrane degradation, and impaired energy management, were observed in the hippocampus and cortex in APP/PS1 mice [13]. Because the metabolic pathways are conserved through evolution [15,16], the metabolic signatures identified in AD mouse models could be directly translated into human studies [17]. Therefore, metabolomics screening in transgenic models could be useful for the understanding of the pathological mechanisms of AD.…”

Specialized Metabolism in a Nonmodel Nightshade: Trichome Acylinositol Biosynthesis

“…limonene and linalool; Dudareva and Pichersky, 2006). As biologically active molecules, specialized metabolites can have adverse effects on the plant making them, and the production or storage of these compounds in specialized structures can mitigate negative effects (Schilmiller et al, 2012b;Schenck and Last, 2020). Epidermal glandular trichomes are an example of biochemical factories that store a wide variety of specialized metabolites across the Plantae kingdom (Fahn, 2000;Schuurink and Tissier, 2020).…”

Enzyme promiscuity and evolution in light of cellular metabolism

“…Promiscuity has mostly been examined in the test tube, where enzymes may accept various substrates and generate different products. However, as discussed by Robert Last and Craig Schenck [6], the physiological impact of an enzyme and of its promiscuity also depends on when and where in the cell an enzyme is expressed. In the living cell, promiscuity generates side products that are deleterious – so‐called damage metabolites.…”