ZINC

Distribution of Zinc in the body

Total body content of Zn is about 2 g in women, 2.5 g in men. Zn is present in all tissues and fluids of the body. 95% is intracellular. Plasma contains only 0.1% of total. Most zinc is in skeletal muscle (57%), then bone (29%).

As the most abundant intracellular trace element, Zn has many different biochemical roles;

• Structural
• Catalytic
• Regulatory

Biochemical roles

Structural:

• Present in cell membranes; may stabilise the membrane by interacting with thiol groups and phospholipids.
• Involved in ribosome stabilisation.
• Stabilises hormone-receptor complexes

Catalytic:

Over 200 Zn enzymes (requiring Zn for full catalytic activity) are known. E.g.

• carbonic anhydrase
• Cu,Zn superoxide dismutase both elements are in the active centre, though Zn doesn’t take an active part in the dismutation process; is it structural?

Regulatory role – gene expression:

Zinc finger proteins are the most common class of transcription factor (i.e. involved in the regulation of gene expression).

Zinc finger

Typically, the Zn finger is a sequence of about 30 amino acids including 2 cysteines (in a beta-sheet hairpin), 2 histidines (on an alfa-helix), and 3 hydrophobic residues, all at conserved positions.
The interaction of Cys and His sidechains with Zn holds the beta-hairpin and alpha-helix tightly together.
The alpha-helix binds in the major groove of the DNA molecule. Each Zn finger recognises a 3-base-pair sequence.
Several Zn fingers may be present in one protein, giving a high level of specificity in sequence recognition.

Zinc and metallothionein

Metallothioneins are nonenzymatic proteins, rich in SH groups, that bind metals, notably Zn, Cu and Cd.
Each molecule can bind up to 12 metal atoms.
MTs sequester surplus metal ions, play a role in metal storage, and are concentrated in the liver.
A high level of Zn in the diet induces intestinal MT. Cu binds to MT more strongly than does Zn. So when MT in the intestinal wall is high, Cu is sequestered rather than taken up in an available form.

In the acute phase response to infections, zinc is redistributed from the circulating blood to intracellular sites. This is related to increased synthesis of intracellular Zn-binding MT, transcriptionally regulated by interleukin 1 (cytokine mediator of events during infection and inflammation).

Zinc absorption

Does MT play a (positive or negative) role in intestinal Zn absorption?

Experiments to measure Zn in serum 2 h after tube-feeding of a single oral dose of Zn to

• transgenic mice, overexpressing MT: serum Zn was one-third lower than in the controls
• knockout mice (no expression of MT-1 or MT-2): serum Zn was twice as high as in the controls.
  Serum Zn was inversely related to level of MT protein.

So MT reduces the efficiency of Zn absorption at elevated zinc intake levels.

Zinc – mode of action

Some effects of zinc in humans (and in animals) seem to be mediated through hormonal action,
since zinc is part of some transcription factors, e.g. the nuclear receptors:

Nuclear Receptors
A characteristic of all nuclear receptors is that each protein contains two zinc fingers. Thus, zinc is involved in hormone signalling of lipophilic hormones since it is integral part of nuclear hormone receptors. Examples of lipophilic hormones that activate specific nuclear receptors:

• sex hormones
• thyroid hormones
• corticosteroids

Nuclear receptors regulate gene expression
In this example, the estrogen receptor (ER) is activated by its ligand estradiol. Activated ER binds to a specific response elenemt (RE) in front of the target gene.
This leads to regulation of the expression of the target gene.

Zinc availability influences membrane signalling pathways for peptide hormones, e.g.

• insulin (biosynthesis and storage)
• growth hormone and IGF1 (insulin-like growth factor 1)
• gonadotropins (FSH, LH)
• prolactin