Nebraska Redox Biology Center Educational Portal


Manganese (Mn) is an essential trace element required for a variety of cellular processes, essential for normal cell growth and development, but is toxic at excess conditions. Manganese may exists in 11 different oxidation states ranging from 3- to 7+. Oxidation states 2+ and 3+ are prevalent and most relevant forn biological system [ 1, 2, 3, 4, 5 ]. A veraety of functionally distinct metalloproteins require manganese for function, including oxidoreductases, DNA and RNA poly-merases, peptidases, kinases, decarboxylases, and glycosyl transferases. Manganese dependant processes are involved 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. [ 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ].

Humans obtain their manganese primarily from drinking water and plant food. Manganese in drinking water and supplements may be more bioavailable than manganese from food. Recommended Mn daily intake is reported to be in the range 0.6-1.5mg/day for childrens and 1.9-2.6mg/day for adults. Manganese toxicity has been reported to occur within the range of greater than 2-3mg/day for childrens and 2-3mg/day for adults [ 16, 17 ].

Map of soil manganese content in the U.S. (red = high manganese areas). Courtesy of U.S. Department of the Interior, U.S. Geological Survey, Mineral Resources.

Only a small percentage of dietary manganese is absorbed. Systemic homeostasis of manganese is maintained by transport across enterocytes at intestinal wall and by its efficient removal by liver. At the cellular level, manganese balance is managed by controlling cellular uptake, retention, and excretion. Manganese is taken up from the blood by the liver and transported to extrahepatic tissues by transferrin and possibly alpha-2-macroglobulin [ 5, 18, 19 ]. Cells are transport manganese AS divalent cation and several classes of manganese transporters have been characterized to date. They include Nramp H+-manganese transporters [ 20 ], ATP-binding cassette (ABC) manganese permeases [ 21, 22 ], manganese transporting P-type ATPases [ 23, 24 ], cation diffusion facilitators (CDFs) [ 25, 26, 27 ] and inorganic phosphate transporters with high affinity for Mn-HPO4 complexes [ 28, 29 ].

Nramp MntH and ABC-type manganese permeases MntABCD/SitABCD are the major manganese transportes in prokaryotes. These manganese transporters are regulated primarily on transcriptional level by MntR transcription factor [ 19 21, 27, 30 ].

Typical manganese transporters in bacterial cells. (A) During conditions of manganese deficiency the high affinity transporters MntH, MntABCD, and MntP facilitate manganese uptake. These manganese transporters are not present in all bacterial species. (B) Manganese excess inhibits expression of the high affinity transporters and induces the manganese efflux protein MntE. Uptake of manganese-phosphate complexes may be a source of manganese when cells are exposed to toxic concentrations of this metal [ 19 ].

In contrans to prokaryotes, eukaryotes do not have the ABC-type manganese permeases and use Nramp family of transporters (SMFs). Intracellular transport of manganese in eukaryotes is mediated by several additional transport systems such as the Golgi transporter Pmr1p. Regulation of eukaryotic manganese uptake occur on post-translational steps through transporters degradation in response to sufficient or excess of Mn [ 19 31, 32, 33 ].

Manganese trafficking in the yeast S. cerevisiae. The eukaryotic yeast cell requires manganese uptake systems as well as transporters to move manganese in and out of intracellular compartments. The high affinity manganese uptake system is comprised of Smf1p and Smf2p, with Pho84p only functioning as a manganese importer during conditions of manganese excess. Intracellular transporters have been identified for the Golgi apparatus and vacuole. Pmr1p imports manganese into the Golgi as well as facilitating exocytic efflux of excess manganese. Atx2p appears to mobilize manganese from the Gogli back to the cytosol. Ccc1p is a vacuolar manganese importer that functions to limit cytosolic manganese concentrations during conditions of excess. Vacuolar manganese exporters and mitochondrial manganese importers have not been identified [ 19 ].

Post-translational regulation of S. cerevisiae Smf1p and Smf2p. Curved arrows indicate the direction of Smf1p and Smf2p trafficking and straight arrows show Mn transport. Thickness of the arrows shows the relative proportion of proteins that are targeted to the indicated intracellular location. (A) Smf1p and Smf2p are highly abundant when manganese is deficient for cellular needs, and they facilitate manganese uptake. (B) When environmental manganese concentrations are sufficient to provide adequate metal for the cell the majority of Smf1p and Smf2p is degraded in the vacuole. Newly synthesized Smf1p and Smf2p are directed from the secretory pathway (Golgi) toward the vacuole for degradation. (C) Excessive or toxic concentrations of manganese result in the removal of the residual Smf1p and Smf2p proteins. Smf1p that is present at the plasma membrane is rapidly internalized and degraded. However, Smf1p and Smf2p in intracellular vesicles are slowly directed to the vacuole for degradation [ 19 ].

Superoxide dismutase (SOD) represents a group of enzymes that use metal cofactor (nickel, iron, manganese, or copper/zinc ions). Superoxide dismutase detoxify superoxyde by catalyzing its dismutation. One superoxide molecule is being oxidized to O2 and another is reduced to H2O2. In the first step of reaction the ion metal is reduced by superoxide which loses its electron and is converted to molecular oxygen. As result, metal cofactor changes oxidation state (Ni3+ → Ni2+, Fe3+ → Fe2+, Mn3+ → Mn2+ and Cu2+ → Cu1+). In second step of reaction the ion metal is oxidized by superoxide which accept electron from tetal and is converted to hydrogen peroxyde (Ni2+ → Ni3+, Fe2+ → Fe3+, Mn2+ → Mn3+ and Cu1+ → Cu2+). As result, the enzyme is returned to its initial reactive state [ 34, 35, 36, 37, 38 ].

MnSOD was identified in the cytosol of archaea and bacteria, and eukaryotic cells typically contain MnSOD in the mitochondrial matrix. In many eukaryotic organisms, such as humans and Saccharomyces cerevisiae, MnSOD is located exclusively in the mitochondrial matrix, while in Candida albicans and many crustaceans, an additional isoform of MnSOD is present in the cytosol. Similarly, plant cells express additional MnSODs in their peroxisomes and chloroplasts. MnSODs have monomers of ~200 amino acids and occur as dimers or tetramers [ 35, 39, 40, 41 ].

Mn3+ + O2.- + H+ → Mn2+ + O2 ;
Mn2+ + O2.- + H+ → Mn3+ + H2O2 ;

Crystal structure of Mn(III) superoxide dismutase from Thermus thermophilus (MnSOD) . Mn atoms are shown as blue spheres. .

H2O2 can be dagraded enzymatically by its reduction to water with by thiol peroxidases (Peroxiredoxins and Glutatione Peroxidases) and metalloenzyme-mediated disproportionation to O2 and H2O. Such metalloenzymes are known as catalases. Peroxiredoxins and glutathione peroxidases are known to eliminate low concentrations of H2O2, whereas catalases are more efficient at higher concentrations of H2O2. [ 42, 43, 44, 45 ]. There are three catalase protein families that are able to catalyze H2O2 disproportionation: (I) typical or monofunctional heme containing catalases, (II) heme containing catalase-peroxidases and (III) non-heme manganese catalases [ 44, 46, 47, 48 ].
Non-heme manganese catalases are minor group of catalases distributed over bacteria and archaea. This type of enzymes represent an important alternative to heme-containing catalases in antioxidant defense. Manganese catalases contain a binuclear manganese complex as their catalytic active site instead a heme. The reactive mechanism is base on cycling between (Mn2+, Mn2+) and (Mn3+, Mn3+) states during turnover [ 49, 50, 51, 52, 53, 54 ]. The (Mn2+, Mn2+) cluster is involved in polarization of the peroxide O-O bond, resulting in cleavage of the peroxidic bond and release of water. Then, (Mn3+, Mn3+) cluster is catalizing oxidation of hydrogen peroxide and oxyden release. The dimanganese cluster is equally stable in either (Mn2+, Mn2+) or (Mn3+, Mn3+) oxidation states. Hydrogen peroxyde degradation rate for manganese catalases is lower compared with typical catalases and catalase-peroxidases [ 49/a>, 52, 53, 54 ].

Catalase-(Mn2+, Mn2+) + H2O2 + 2H+ → Catalase-(Mn3+, Mn3+) + 2H2O ;
Catalase-(Mn3+, Mn3+) + H2O2 → Catalase-(Mn2+, Mn2+) + O2 ;

Crystal structure of homohexamer of manganese catalase from Lactobacillus plantarum. Mn atoms are shown as blue spheres.

Bacterial ring-cleaving dioxygenases are critical enzymes in the catabolism of aromatic compounds. Dioxygenases that act on ortho-dihydroxylated aromatic substrates are divided into intradiol and extradiol dioxygenases. They differ in their mode of ring cleavage and the oxidation state of the active-site metal. Extradiol dioxygenases are Fe2+ or Mn2+ dependant and cleave one of the carbon-carbon bonds adjacent to the ortho-hydroxyl substituents [ 55, 56 ].

Crystal structure manganese-dependent homoprotocatechuate 2,3-dioxygenase from Arthrobacter globiformis. Mn atoms are shown as blue spheres.

Ribonucleotide reductases catalyze the conversion of ribonucleotides to corresponding deoxyribonucleotides in all living organisms and are essential for DNA replication and repair. Ribonucleotide reductases class Ib use a dimetal-tyrosyl radical cofactor in their NrdF (β-2) subunit to initiate ribonucleotide reduction in the NrdE (α-2) subunit. Enzyme activity requires a dimanganese tyrosyl radical (Mn23+-Y.). This radical is generated from the Mn22+ in a self-assembly process in the presence of O2 and the flavodoxin-like protein NrdI [ 57, 58 ].

NrdEF is the ribonucleotide reductase enzyme [ 59 ].

Crystal structure of Mn-dependant Ribonucleotide Reductase from Bacillus cereus. Mn atoms are shown as blue spheres.

Oxalate oxidase is enzyme involved in the production of hydrogen peroxide for lignin degradation and cell wall crosslinking. This enzyme catalyzes the conversion of oxalate and oxygen to carbon dioxide and hydrogen peroxide [ 60, 61 ].

Oxalate oxidase + O2 + 2H+ → 2CO2 + H2O2 ;

Proposed free-radical mechanisms for oxalate oxidation and decarboxylation [ 60 ].

Crystal structure of Mn-dependant oxalate oxidase from Hordeum vulgare. Mn atoms are shown as blue spheres.

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