MAGNESIUM

An abundant element: body contains around 25 g.
Most is in bone, then muscle, and soft tissue.
Concentration within cells is about 1 mM.

Most of the total intracellular Mg is bound to ligands:

• ATP
• ADP
• citrate
• proteins
• nucleic acids

About 5-10% is free Mg²⁺.

Within the cell, Mg is compartmentalised – to the:

• mitochondria
• nucleus
• ER

The concentration of free Mg²⁺ outside the cells is much higher than inside.

• Na⁺-dependent efflux maintains the intracellular level, and regulation is subject to external stimuli (e.g. hormones).
• It is also affected by intracellular cAMP levels and protein kinase C activity.

Biological roles (enzymic)

Mg is an essential co-factor in many enzymic reactions, participating in two ways:

Association with substrate

Associates notably with ATP and ADP; Mg-ATP and Mg-ADP are the true substrates for the respective enzymic reactions. Mg-ATP is the energy provider for virtually all cellular processes.

Directly participating in the enzymic action

Mg binds only weakly to enzyme active sites, and so in in vitro biochemical experiments with the enzymes, it is normally necessary to add Mg.
Mg is involved in the reaction of a large number of enzymes. They are too numerous to list, but include

• the large number of enzymes using ATP (or ADP) as a substrate – including energy metabolism
• DNA polymerases, DNA repair enzymes etc.
• Adenylate cyclase (converting Mg-ATP to cAMP, an intracellular messenger)
• Protein kinases (transferring phosphate from Mg-ATP to many proteins involved in cell signalling).
• Ubiquitin-proteosome pathway of protein breakdown

Biological roles (structural)

• Mg²⁺ associates strongly with the phosphate groups of polynucleotides, RNA, DNA (cf ATP, ADP) – 0.2 mole of Mg²⁺ per mole of phosphate.

• Mg²⁺ stabilises the DNA double helix. Critical levels of Mg²⁺ are needed to maintain (hetero)chromatin structure.

• Free Mg²⁺ and GTP-Mg play an essential role in tubulin polymerisation and thus in chromosome segregation during mitosis.

Apoptosis

Free intracellular magnesium rises in cells undergoing apoptosis (mobilised from mitochondria). This occurs before (and may therefore be a signal for) DNA fragmentation.
Ca²⁺ and Mg²⁺-dependent endonucleases are involved in the DNA fragmentation itself.

DNA replication

The various DNA polymerases in eukaryotes all require magnesium ions for efficient DNA replication.
Although Co²⁺, Mn²⁺ or Ni²⁺ can substitute for Mg²⁺ in the reaction, there is a marked decrease in replication fidelity. The magnesium ions help to position the incoming nucleotide and promote phosphate transfer (hydrolysis of the triphosphate).
Magnesium is also involved in the reactions of topoisomerases – enzymes that make transient breaks in DNA strands to allow other strands to pass through them (making or relaxing supercoils).

DNA repair

Many of the enzymic steps in DNA repair are Mg-dependent, e.g.

• damage recognition, helicase, incision, polymerisation, ligation (nucleotide excision repair – NER)
• AP-endonucleases in base excision repair (BER)
• mismatch repair proteins
• double strand break repair (homologous recombination).