Manganese Transport, Trafficking and Function in Invertebrates

AMORNRAT NARANUNTARAT JENSEN AND LARAN T. JENSEN

1.1 Introduction

Manganese is a biologically important trace metal and is required for the growth and survival of most, if not all, living organisms. It is perhaps best known for its prominent role as a redox-active cofactor in free radical detoxifying enzymes. However, the utilization of manganese in biological systems is substantially more diverse. The uptake and distribution of manganese is critical for proper function of manganese-requiring enzymes; however, this same metal can have deleterious effects in biological systems if homeostasis is disrupted. In order to prevent toxicity, cells maintain manganese under tight homeostatic control. Adding complexity to the cellular control of manganese homeostasis is the presence of multiple types of manganese transporter that participate in the specific transport of manganese or in general divalent metal ion transport.

Cells appear to transport manganese solely as the divalent cation and several classes of manganese transporters have been characterized. These include Nramp H+-manganese transporters, ATP-binding cassette (ABC) manganese permeases, manganese transporting P-type ATPases, cation diffusion facilitators (CDFs), and inorganic phosphate transporters with high affinity for Mn-HPO4 complexes. Bacteria typically contain one or more of these types of transporter, and these classes of transporter are also present in eukaryotic cells. These transporters comprise both high and low affinity manganese uptake systems and the transporter utilized depends on the concentration of manganese in the environment. The homeostatic range for manganese is quite wide, with cellular levels of manganese between 0.04 and 2.0 mM under optimal growth conditions. Cells rarely experience optimal environmental levels of manganese and often face extreme conditions of either manganese deficiency or excess. Cells activate stress response mechanisms in an attempt to return manganese levels to the homeostatic range. The response typically results in the upregulation or downregulation of cell surface and intracellular transport systems. The regulation of manganese uptake, distribution, and efflux can occur at both the transcriptional and post-translational levels, although the specific route of regulation varies in different organisms.

1.2 Function of Manganese in Biological Systems

1.2.1 Manganese Metalloenzymes

Manganese metalloenzymes are involved in a wide range of cellular functions, including detoxification of reactive oxygen species, protein glycosylation, polyamine biosynthesis, DNA biosynthesis, nucleic acid degradation, phospholipid biosynthesis and processing, polysaccharide biosynthesis, protein catabolism, the urea cycle, photosynthesis, and sugar catabolism. Manganese-dependent enzymes that participate in these processes typically utilize manganese in Lewis acid-base reactions or as a reduction/oxidation center to facilitate catalysis. These types of reaction are exemplified by arginase (Lewis acid) and Mn superoxide dismutase (reduction/oxidation), and the role of manganese in these reactions is shown in Figure 1.1.

1.2.2 Non-Protein Manganese Antioxidants

The importance of manganese in biological systems is not limited to enzyme-mediated catalysis. Non-enzymatic manganese is involved in the formation of bacterial products, including secreted antibiotics, and contributes to the stabilization of bacterial cell walls. In addition, the accumulation of non-protein complexes of manganese can function in the removal of reactive oxygen species (ROS), especially superoxide. These Mn-antioxidants are divalent manganese complexes of small metabolites, and while the nature of the intracellular Mn-complexes has not been clearly defined, phosphate and lactate Mn-complexes have been shown to display the capacity to react efficiently with superoxide in vitro. Complexes of both iron and copper exhibit superoxide scavenging activity, however these metal ions also exhibit pro-oxidant activity. In contrast, manganese ions react poorly with hydrogen peroxide and do not generate the highly toxic hydroxyl radical, providing a beneficial antioxidant activity without the pro-oxidant side effects of other redox active metals.

It appears that Mn-antioxidants can serve to enhance oxidative stress protection when enzymatic antioxidants are insufficient in various organisms. A critical role for Mn-antioxidants has been demonstrated in Deinococcus radiodurans, a bacterium that is extremely resistant to radiation and desiccation. In this organism, survival under extreme exposure to radiation and other oxidative stress conditions is not dependent on antioxidant enzymes but instead relies on the accumulation of millimolar concentrations of manganese and the subsequent formation of Mn-antioxidants. Interestingly, Lactobacillus plantarum, while resistant to oxidative stress, does not express the antioxidant enzyme superoxide dismutase. Indeed, L. plantarum appears to rely exclusively on Mn-antioxidants for protection against oxidative stress, highlighting the power of this alternative ROS detoxification pathway.

The majority of the information on manganese antioxidants has come from investigation of bacterial and yeast systems; however, it is also likely that these complexes are present in multicellular organisms. Elevated manganese accumulation in the...