Metabolism Shapes the Cell

Abstract

More than 5 decades of work support the idea that cell envelope synthesis, including the inward growth of cell division, is tightly coordinated with DNA replication and protein synthesis through central metabolism. Remarkably, no unifying model exists to account for how these fundamentally disparate processes are functionally coupled. Recent studies demonstrate that proteins involved in carbohydrate and nitrogen metabolism can moonlight as direct regulators of cell division, coordinate cell division and DNA replication, and even suppress defects in DNA replication. In this minireview, we focus on studies illustrating the intimate link between metabolism and regulation of peptidoglycan (PG) synthesis during growth and division, and we identify the following three recurring themes. (i) Nutrient availability, not growth rate, is the primary determinant of cell size. (ii) The degree of gluconeogenic flux is likely to have a profound impact on the metabolites available for cell envelope synthesis, so growth medium selection is a critical consideration when designing and interpreting experiments related to morphogenesis. (iii) Perturbations in pathways relying on commonly shared and limiting metabolites, like undecaprenyl phosphate (Und-P), can lead to pleotropic phenotypes in unrelated pathways.KEYWORDS FtsZ, MreB, UDP-glucose, cell division, gluconeogenesis, metabolism, morphogenesis, peptidoglycan, phosphoenolpyruvate, undecaprenyl phosphate T o accurately partition chromosomes and other cell contents during reproduction, cells must possess mechanisms to organize repeated cycles of cell growth, chromosome replication, and division. Eukaryotes orchestrate this coordination using the cell cycle and separate growth, DNA synthesis, and cytokinesis into distinct, temporally sequestered phases. Bacteria, by contrast, simultaneously increase in cell size and replicate DNA before (or concurrently with) cell division. Elucidating the molecular mechanisms prokaryotes employ to achieve spatiotemporal organization of these intertwined yet functionally disparate processes is of considerable interest to scientists seeking to understand bacterial reproduction, and many outstanding questions remain to be answered. For example, how is DNA replication kept in sync with changing growth and division rates? How are cell dimensions maintained or actively rearranged in response to environmental or developmental cues? What signals do cells sense to switch between increasing in cell size and dividing during the cell cycle? Relatedly, how are these signals transduced to activate/deactivate the distinct machineries required for each process?Perhaps one of the biggest mysteries remaining in bacterial cell biology relates to understanding the regulatory cross talk that must occur to integrate central metabolism with macromolecular biosynthesis. Nutrients are converted into stored energy and precursors used to synthesize macromolecules like DNA and peptidoglycan (PG), so it is no surprise that nutrient availability has a profound impac...

Metabolic response to point mutations reveals principles of modulation of in vivo enzyme activity and phenotype

“…Unlike eukaryotic cells which have distinct stages of cell cycle and growth, prokaryotes like E. coli coordinate cytoplasmic growth, DNA replication and cell division simultaneously to achieve balanced growth. It has been argued that it is cellular metabolism that efficiently coordinates these processes (Sperber and Herman, 2017). Several metabolic pathways, for example TCA cycle (Monahan et al, 2014), nitrogen metabolism (Beaufay et al, 2015), pyruvate metabolism (Monahan et al, 2014), glucose metabolism (Hill et al, 2013;Weart et al, 2007), etc., have been implicated to control cell shape and size.…”

“…However, mutations (or other loss of function such as inhibition by an antibiotic) in metabolic enzymes are also known to cause filamentation (Fonville et al, 2010;Sperber and Herman, 2017). A well-studied example is thymineless death (TLD) where cells acquire filamentous phenotype upon severe deprivation of essential metabolite thymine (Ahmad et al, 1998).…”

The cell cycle in Staphylococcus aureus is regulated by an amidase that controls peptidoglycan synthesis

“…In its absence, cells grow larger than normal, resulting in division defects. The genetic connection between ActH and Noc, and the linkage between metabolism genes and lytH / actH , reinforce the importance for cell division of ensuring that cell wall synthesis is properly integrated with primary metabolic pathways inside the cell 29–31 .…”

Movement Dynamics of Divisome and Penicillin-Binding Proteins (PBPs) in Cells of Streptococcus pneumoniae

“…On the other hand, the velocity of FtsZ treadmilling is not correlated with the rate of PG synthesis determined by FDAA incorporation or the rate of septum closure of Eco cells (13, 52). These differences suggest that additional metabolic (e.g., PG precursor pools) and structural (e.g., PG width and outer membrane synthesis) constraints may influence the relative rates of FtsZ treadmilling, bPBP complex movement, and PG synthesis in different bacteria (53, 54).…”