Zinc metabolism
Zinc

Zinc is a chemical element with the atomic number 30, represented by the chemical symbol Zn.

Linus Pauling Institute

Zinc is an essential element in the nutrition of human beings, animals, and plants. Zinc is required in the genetic make-up of every cell and is an absolute requirement for all biologic reproduction. Zinc is needed in all DNA and RNA syntheses and is required at every step of the cell cycle. DNA is about 5000 times less susceptible to damage by Zn2+ ion than is RNA, suggesting its role in the predominant evolutionary selection of DNA, rather than RNA, as the bearer of the primary genetic information.

In prebiotic chemistry on Earth billions of years ago, zinc most likely was the first effective nonenzymatic polymerase. Zinc remains an essential component of all DNA and RNA polymerases examined today. With a poly C template, Zn2+ alone can catalyze the assembly of an activated GMP derivative (guanosine 5’-phosphoimidazolide) into poly G chains 30 to 40 residues in the natural 3’-5’ linkage. Although other metals are catalytic, Zn2+ ion produces greater fidelity.

Zinc Finger are finger-like protrusions extending from transcription factors or gene-regulating proteins and fastening to the wide, major groove of a DNA molecule. Since the discovery of zinc fingers in 1985, over 200 proteins, many of which are transcription factors, have been found to incorporate zinc fingers. Zinc fingers rely totally upon Zn2+ ions for their form and function. Zinc fingers have been identified in species as diverse as yeast to human beings. About 1 percent of the DNA in human cells specify zinc fingers. As few as 2 and as many as 37 zinc fingers occur on gene-regulating proteins. Zinc fingers are believed to enable enzymes to transcribe a second genetic segment from DNA into RNA serving as a template for synthesis of a specific protein such as a string of amino acids or RNA itself. The finger-like projections are perfectly suited for DNA recognition by means of their three-dimensional shape. From an evolutionary standpoint, ancestral genes specifying a small protein of 30 or so amino acids would easily pick up zinc from the environment and would fold without assistance into a stable conformation where they would have the ability to bind to DNA and RNA.

GENERAL ZINC BIOCHEMISTRY

The dietary intake of zinc is around 10-15 mg/day. It is present in meat and other protein foodstuffs, but intestinal absorption is affected by other dietary constituents . About 3 grams of zinc is distributed throughout the body (average 10 to 200 mmg/gram) of an adult human being. Absorption of dietary zinc occurs over the duodenal and jejunal regions of the gastrointestinal tract. Active transport of zinc into portal blood is mediated by metallothionein. Zinc competes with other metals for absorption, and absorption is believed greatly retarded by ingestion of fiber and phytates.
Plasma zinc is complexed to organic ligands. Zinc-albumin complexes account for about 50 percent of the zinc, and the metal is readily exchangeable throughout the peripheral circulation. About 7 to 8 percent is loosely bound to amino acid constituents in plasma. The remaining 40+ percentage of plasma zinc is largely bound to macroglobulins and unavailable for nutritional purposes. Serum and plasma zinc concentrations in adults range from 80 to 150 mmg/dL, although circadian diurnal fluctuations occur in concentration.Circadian diurnal variation peaks at 9:30 AM and reaches a low at 8 PM with differences of 19 mmg/dL.Rather than an enterohepatic circulation, zinc experiences a similar enteropancreatic recycling.

Circadian variations in serum zinc (Zn) concentrations: correlation with blood ionized calcium, serum total calcium and phosphate in humans, 1985.

An amount of zinc equivalent to the total absorbed zinc is re-excreted into the gut in intestinal fluids. In normal health zinc output by the gut is equal to the total dietary intake. Urinary excretion of zinc is low (around 10 µmol/day), and does not vary markedly with dietary supply. It is increased in catabolic states, by certain drugs and/or chelating agents.

Figure 1:
Zinc metabolism in adult man. Intake, absorption, intestinal endogenous excretion and zinc losses via faeces, urine and skin are given in mg/day. Estimates of total zinc content (mg) of organs and tissues indicated.

HOW AND WHERE IS ZINC ABSORBED/PROCESSED IN HUMAN BODY?

Oysters, shellfish, red meats, liver, and egg yolks are rich sources of dietary zinc. Wholegrains, nuts, legumes, and pumpkin seeds are relatively good plant sources.
In general, zinc from meat sources has a higher bioavailability due the presence of amino acids (such as glycine, histidine, lysine, methionine, and cysteine) that improve zinc absorption. Other compounds known to enhance zinc absorption include picolinic acid (secreted by the pancreas), vitamin B6 (increases picolinic acid secretion), and citrate.
The zinc in wholegrain products and other plant sources is less bioavailable because of their high content of phytic acid, a compound that inhibits zinc absorption, and fibre. In addition to fibre and phytates, minerals such as calcium, iron, copper and manganese have been shown to reduce zinc absorption by competing for transport across the brush border membrane.

ZINC ENZYMES

Zinc is an integral component of about 300 enzyme, within the enzymes, the role of zinc can be catalytic, co-catalytic and structural:

Catalytic function: when the ion Zn 2 + is directly involved in catalysis and its
deletion causes loss of enzyme activity.

Co-catalytic function: 2 or 3 metals are needed in order for the enzyme to fulfill its
function. Zn occupies a position very close to another metal center with which
joined through a bridge formed by a single amino acid or through a molecule of H2O (Cu, Zn-SOD).

Structural function: the ion is necessary to maintain tertiary structure and in some cases the quaternary of the apoenzyme, (metalloproteins involved in the regulation of gene expression: zinc-fingers proteins).

Catalytic function:

• Carbonic anhydrase,
  catalyses the rapid interconversion of carbon dioxide and water to bicarbonate and protons (or vice-versa) and so it is essential for respiration.
  A zinc prosthetic group in the enzyme is coordinated in three positions by histidine side-chains. The fourth coordination position is occupied by water. This causes polarisation of the hydrogen-oxygen bond, making the oxygen slightly more negative, thereby weakening the bond.
  A fourth histidine is placed close to the substrate of water and accepts a proton, in an example of general acid-general base catalysis. This leaves a hydroxide attached to the zinc.
  The active site also contains specificity pocket for carbon dioxide, bringing it close to the hydroxide group. This allows the electron rich hydroxide to attack the carbon dioxide, forming bicarbonate.

• Alcohol dehydrogenases,
  are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+ to NADH).
  They are dimeric proteins, with each subunit binding two Zn ions, only one of which is catalytically active. This catalytic Zn ion has distorted tethrahedral geometry, coordinated to one histidine and two cysteine residues. The non-catalytic zinc plays a structural role and is coordinated tethahedrally to four cysteine residues.

• Proteases
  • Carboxypeptidase,
    is a protease enzyme that hydrolyzes (cleaves) the peptide bond of an amino acid residue at the carboxy-terminal (C-terminal) end.
    Humans, animals, and plants contain several types of carboxypeptidases which have diverse functions ranging from catabolism to protein maturation.
  • Insulin protease or Insulin Degrading Enzyme,
    is a thiol zinc-metalloendopeptidase located in cytosol, peroxisomes, endosomes, and on the cell surface that cleaves small proteins of diverse sequence, is the major enzyme responsible for insulin degradation in vitro. It was recently shown that transferring an ≈3.7-cM chromosomal region containing the IDE gene from an inbred rat model of type 2 diabetes mellitus (DM2) (the GK rat) to a normoglycemic rat recapitulated several features of the diabetic phenotype, including hyperinsulinemia and postprandial hyperglycemia.
    Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo, 2002.
    IDE is also a key molecule in the pathogenesis of Varicella-zoster virus (VZV).It plays a role as a receptor through its unique amino terminal extracellular domain, binding viral glycoprotein E (gE), essential for virus infectivity.
    Insulin Degrading Enzyme Induces a Conformational Change in Varicella-Zoster Virus gE, and Enhances Virus Infectivity and Stability, 2010..

Co-catalytic function:

• Superoxide dismutases
  are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide, playing an important role as antioxidant defense in nearly all cells exposed to oxygen.
  In particular, SOD1 contain copper and zinc and its structure consists of two subunits of identical molecular weight joined by a disulfide bond.There are two Cu2+ and two Zn2+ atoms per molecule.
  Zinc has a structural and stabilizing role while Cu2+ is directly involved in the catalytic activity.
  Both zinc and copper are co-factors that is an important scravenger of superoxide radicals.

Structural function:

• Zinc finger has got an anti-parallel hairpin motif. It consists of 2 beta strands, one alpha helix and a hairpin structure. Zn is buried in the interior of the protein and it is necessary for the formation of a stable finger structure in aqueous solution. The zinc does not interact with DNA, the structure is surrounded by several hydrophobic residues that confer additional stability.
  Zinc Fingers are present among proteins that perform a wide range of cellular functions including replication and repair, transcription and translation, metabolism, proliferation, and apoptosis.

The structure and function of cell membranes are also affected by zinc. Loss of zinc from biological membranes increases their susceptibility to oxidative damage and impairs their functioning.

• zinc plays a structural role in the storage of insulin: binds six molecules of insulin with the involvement of histidine residues (Insulin is stored in the body as a hexamer, while the active form is the monomer).

• HIV Vif protein

HUMAN ZINC DEFICIENCY

Human zinc deficiency was first described in Iran in the early 1960s by Prasad and colleagues. They observed that zinc-deficient patients displayed symptoms of "severe growth retardation, anemia, hypogonadism, hepatosplenomegaly, rough and dry skin, mental lethargy and geophagia."

Zinc deficiency in human subjects, 1983

Marginally zinc-deficient patients display numerous non-specific symptoms, such as growth retardation, skin changes, vulnerability to infections, and delayed wound healing. On the other hand, severe zinc deficiency is rare in developed countries. It's usually caused by inborn defects of zinc absorption or secondary factors, including liver disease, chronic renal disease and sickle-cell disease. The affected patients suffer from severe dysfunctions of the central nervous, immune, reproductive, epidermal, and skeletal systems.

Signs of zinc deficiency include: hair loss, skin lesions, diarrhea, and wasting of body tissues. Zinc has also a function on the hepatic metabolism of vitamin A, it is an excellent anti-degenerative and anti-inflammatory, a catalyst of pituitary function, participates in the processing (catalyzing the reactions of exoprotease carboxypeptidase E ), storage and use of insulin.
The Gustin is a hormone linked to the zinc; in fact, its lack induces loss of the sense of taste.
Moreover, in Timoline, zinc performs an action on the immune system and stimulates growth hormone.
A reduced activity of carbonic anhydrase, due to zinc absence, was reported in gastric and intestinal problems.
At least, its deficiency is evident in spermatogenesis: the collapse of testosterone is caused by an excessive role of aromatase that converts testosterone into estrogen, creating an imbalance between the two hormones.

Zinc deficiency and cancer

Zinc deficiency impairs DNA integrity and, thus, increases the cell susceptibility to abnormal growth.
DNA damage can be caused by numerous endogenous and exogenous agents, such as ionizing radiation, ultraviolet light, reactive oxygen species, ethidium bromide, and food-borne carcinogens (polycyclic aromatic hydrocarbons and heterocyclic amines).
In addition, deficiencies of micronutrients like vitamin C, vitamin E, iron, and zinc may damage DNA through breaks or oxidative modifications.
Two mechanisms are likely involved in the effect of zinc deficiency on DNA damage:
First, zinc deficiency compromises the functions of the zinc-containing antioxidant enzyme, copper-zinc superoxide dismutase, and increases oxidative stress (direct DNA damage).
Second, zinc deficiency impairs DNA repair functions by interfering with the activities and expression of DNA repair proteins.
Accordingly, zinc-deficient cells undergo a double hit-DNA damage and the ability to repair it is compromised.

BENEFITS OF ZINC

MUCOUS MEMBRANE HEALTH

• Gastrointestinal tract (Crohn's disease)
• Respiratory tract (Synergistic effects of vitamin A and zinc)

IMMUNITY AND INFECTIONS

• Viral infections (Cold and Flu, Herpes Simplex)
• Parasitic infections
• Zinc, immunity and the elderly

MUSCULOSKELETAL

• Osteoporosis
• Rheumatoid arthritis

NEUROLOGICAL CONDITIONS

• Attention deficit hyperactivity disorder
• Dementia/ Alzheimer’s disease
• Other neurological conditions

REPRODUCTIVE HEALTH

• Male fertility
• Prostate health
• Zinc requirements in pregnancy

GROWTH AND DEVELOPMENT

• Growth and weight gain
• Neural and motor development

SKIN AND HAIR

• Acne vulgaris/ Acne rosacea
• Hair loss
• Warts
• Wound healing

WEIGHT MANAGEMENT AND DIABETES

• Appetite regulation
• Weight management
• Anorexia nervosa
• Diabetes mellitus

OTHER APPLICATIONS

• Eye health
• Hearing/ tinnitus
• Wilson’s disease
• Sickle cell disease

IMMUNITY AND INFECTIONS

One of the most important roles of zinc is to maintain a healthy immune system and thereby help the body to fight off a range of infections, including influenza and the common cold. Zinc affects multiple aspects of the immune system including both non-specific, and specific, immunity.
Non-specific immunity includes the barrier function of the skin and the mucous membrane linings of the gastrointestinal and respiratory tracts, polymorphonuclear leukocyte function, natural killer cell function, and complement activity.
Effects on specific immunity include decreased lymphocyte concentration and suppressed T- and B-lymphocyte functions, including antibody production.
The macrophage, a fundamental cell in many immunologic functions, is also adversely affected by zinc deficiency, which can lead to dysregulation of intracellular killing, cytokine production, and phagocytosis.
The effects of zinc on these key immunologic mediators is rooted in the myriad of roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation.

Zinc and immune function: the biological basis of altered resistance to infection, 1998.

VIRAL INFECTIONS

Zinc has been shown to inhibit the growth of several viruses in vitro, including rhinoviruses, picornaviruses, togaviruses, herpes simplex virus, and vaccinia virus.There are also a growing number of studies indicating the benefits of zinc in HIV and associated opportunistic infections. Low levels of plasma zinc predict a 3-fold increase in HIV related mortality, whereas normalisation has been associated with significantly slower disease progression and a decrease in the rate of opportunistic infections.

Zinc status in human immunodeficiency virus type 1 infection and illicit drug use, 2003.

PARASITIC INFECTIONS

Research has shown that parasites are better able to survive in the zinc-deficient host than in a well-nourished host. Given the paramount role of the gastrointestinal-associated lymphoid tissue in regulating immune responses to intestinal parasites, the researchers concluded that zinc deficiency exerts profound effects on the gut mucosal immune system, leading to prolonged parasite survival.

Zinc deficiency impairs immune responses against parasitic nematode infections at intestinal and systemic sites, 2000.

MUSCULOSKELETAL

An increasing number of zinc finger genes are implicated in bone, cartilage, and tooth development. These zinc finger proteins contain multiple structural motifs that require zinc to maintain their structural integrity and function.
Zinc deficiency is known to result in skeletal growth retardation and has been identified as a risk factor in the pathogenesis of osteoporosis.

Zinc finger transcription factors in skeletal development, 2004.

OSTEOPOROSIS

Zinc is an essential cofactor for enzymes involved in the synthesis of various bone matrix constituents. There is ample evidence that zinc plays an important role in bone metabolism and zinc deficiency has been implicated as a risk factor in the development of osteoporosis. It is believed that zinc deficiency during growth may impair the accumulation of maximal bone mass in humans.

Is there a potential therapeutic value of copper and zinc for osteoporosis?, 2002.

NEUROLOGICAL CONDITIONS

Zinc is essential for healthy brain development and function. Zinc status affects growth and maturation of neurons, synthesis of neurotransmitters, and the function of certain receptors. Deficiency of the nutrient has subtle effects on neuropsychological functions that may not be perceived by the affected individuals and, if severe, can impair thought processes.
Studies suggest that even mild zinc deficiency may decrease cognitive function in adults. Cognition is a field of thought processes by which an individual processes information through skills of perception, thinking, memory, learning and attention. Zinc deficiency may affect cognitive development by alterations in attention, activity, neuropsychological behaviour and motor development.

Zinc and cognitive development, 2001.

ATTENTION DEFICIT HYPERACTIVITY DISORDER

Zinc intake has been found to correlate with social behaviour, activity levels and reading abilities in school-aged children. Some studies suggest that a deficiency of zinc plays a substantial role in the aetiopathogenesis of Attention Deficit Hyperactivity Disorder (ADHD).

ALZHEIMER’S DISEASE (AD)

Zinc deficiency is one of the most common nutrient deficiencies in the elderly and may be a major factor in the development of AD. Most enzymes involved in DNA replication, repair, and transcription contain zinc, and one cause of dementia may be the long-term cascading effects of error-prone or ineffective DNA-handling enzymes in nerve cells.

However, there exists a conflicting theory that zinc may be problematic for Alzheimer’s patients as, in vitro, zinc may accelerate the formation of the insoluble beta-amyloid peptide plaque that is characteristic of the condition. In addition, studies have shown alterations of several zinc transporter proteins in vulnerable brain regions of subjects with mild cognitive impairment and AD, suggesting disruptions of zinc homoeostasis may play a role in the pathogenesis of the disease.

A study of post-mortem neocortical tissue from patients with AD has demonstrated that zinc accumulation in the brain is a prominent feature of advanced AD. Other research has shown a higher concentration of the antioxidant enzyme copper-zinc superoxide dismutase in and around the damaged brain tissue. This may be suggestive of an increased concentration of zinc in the damaged areas due to the body’s efforts to neutralise free radicals.

The exact role of zinc in the progression of AD remains unclear. In one small study, 10 patients with Alzheimer’s disease were prescribed 27mg zinc (as zinc aspartate) daily. 80% showed improvement in memory, understanding, communication, and social contact.

A potential role for alterations of zinc and zinc transport proteins in the progression of Alzheimer's disease, 2009.

REPRODUCTIVE HEALTH

MALE FERTILITY

Zinc is important in several aspects of male reproduction including hormone metabolism, sperm formation, and sperm motility. Normally, zinc concentrations are very high in the male genital organs, particularly in the prostate gland, which is largely responsible for the high zinc content in seminal plasma. Spermatozoa themselves also contain zinc, which is derived from the testis.

The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility, 2007.

Low zinc levels have been found in infertile men with low testosterone levels, oligospermia (low sperm count) and azoospermia (no sperm in semen). Seminal zinc levels have also been noted to correlate with normal morphology (size and shape) of sperm.

Zinc levels in seminal plasma are associated with sperm quality in fertile and infertile men, 2009.

Several studies support the use of zinc supplementation in the treatment of oligospermia, especially in the presence of low testosterone levels.

ZINC REQUIREMENTS IN PREGNANCY

Zinc is considered one of the most important nutrients in pregnancy.

Severe maternal zinc deficiency has been associated with spontaneous abortion and congenital malformations. Milder forms of zinc deficiency have been linked to low birth weight, intrauterine growth retardation, preterm delivery, complications of labour, and need for assisted delivery. These complications in turn impair maternal and perinatal health because they may lead to increased risk of maternal lacerations, high blood loss, maternal infections, foetal distress, stillbirth, neonatal asphyxia, respiratory distress, and neonatal sepsis. These interrelations are shown below.

Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival, 1998.

Zinc deficiency may also adversely affect the infant’s immune system and reduce the transfer of maternal antibodies to the developing foetus during the third trimester.

The developing foetus of a pregnant woman who is low in zinc and high in copper may experience difficulties in early brain development, which may later manifest as schizophrenia, autism or epilepsy.

GROWTH AND DEVELOPMENT

Zinc deficiency impairs growth by decreasing the activity of enzymes that are involved in the synthesis of nucleic acids and proteins, and by decreasing the growth-regulating hormone insulin-like growth factor (IGF) and other growth factors.

DRUG INTERACTIONS

Amiloride is used as a water pill; to help remove excess water from the body, may reduce urinary zinc excretion and lead to zinc accumulation.

Captopril and enalopril
These drugs increase urinary excretion of zinc; monitor for signs and symptoms of zinc deficiency.

Cisplatin
Preliminary data suggest that zinc stimulates tumour cell production of the protein metallothionein which binds and inactivates cisplatin. However, it is not known whether supplemental zinc or high dietary zinc intake can cause clinically significant interference with cisplatin therapy.

Penicillamine is used for Wilson’s disease and rheumatoid arthritis. Zinc might decrease how much penicillamine your body absorbs and decrease the effectiveness of penicillamine.

Radiotherapy reduces plasma zinc levels.

Tetracycline and quinolone antibiotics
These antibiotics form complexes with zinc in the gastrointestinal tract, reducing absorption of both the drug and the nutrient if taken at the same time.

Authors: Daniele Niola and Marcello Salis