LEAD Action News
LEAD Action News vol 8 no 3, 2001, ISSN 1324-6011
Incorporating Lead Aware Times ( ISSN 1440-4966) and Lead Advisory Service News ( ISSN 1440-0561)
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The Chemical Background of Lead Poisoning

By Dr Neville Gibson, MSc, PhD

The neurotransmitter serotonin is responsible for putting us to sleep at night and keeping us in a good mood during the day. It is produced in the brain from the essential amino acid tryptophan and then partially decomposed by enzyme-catalysed reactions as follows: Tryptophan (Tryptophan hydroxylase) 5-Hydroxytryptophan (Aromatic amine acid decarboxylase) Serotonin (Monoamine oxidase) 5-Hydroxyindoleacetic acid. (Clearly the Specific Serotonin Re-uptake Inhibitor or SSRI antidepressants like Prozac depress the final step).

= Converts to

( ) brackets indicate the catalyst

The enzyme involved in at least the first (rate determining) reaction has been shown to be a metalloenzyme with magnesium at the active site (1, 2, 3, 4, 5). Amino acids are all bidentate ligands, so a magnesium ion, which is six-covalent, will bind to two amino acid residues of the enzyme to fold it to form an appropriate cleft, and then be able to weakly bind the tryptophan so it can undergo the catalysed hydroxylation. Tables of stability constants give log KI = 3.5 for magnesium to glycine (which can be taken as a representative amino acid). In general, for a bidentate chelate log K2 = log K 1-1 and log K3 = log K 1-2 (very roughly) so the tryptophan will be held with a bond of strength log K3 = 1.5, weak enough to release the 5 -hydroxytryptophan once formed. The magnesium appears to be present as the ATP adduct, and calcium (log KI to glycine = 1.4) is also involved. The stability constant for lead to glycine is given by log K I =5.5, so the bond from lead to an amino acid is approximately one hundred times stronger than that from magnesium. Thus lead ions can be expected to displace the magnesium ions from the enzyme. Unlike magnesium, lead is four~covalent, so after it has bound to two amino acid residues of the enzyme it cannot bind to tryptophan at all, so the synthesis of serotonin is blocked, and if enough lead ions are present, depression would be expected to result. This has been shown to be the case (6, 7, 8, 9, 10). Cadmium, with a stability constant to glycine of log K I = 4.5 and a covalency of four, would be expected to behave similarly to lead.

There are many enzyme-catalysed reactions in the body, of which the above is but one, albeit a topical one. Many have magnesium at the active site, and so would be blocked by lead in the same way.

Another amino acid-containing molecule in our body which it would seem interesting to consider is phosphatidylserine (PS). This molecule consists of a head of a serine (hydroxyglycine) group joined to a body of a phosphate group and a glycerol residue, in turn joined to a tail of two fatty acid groups. The function of PS is to bridge the synapse between two neurons (of which there are very many) in the brain, thus enabling memory, concentration, and all cognitive processes. I have not seen any description of just how this bridging is effected at the molecular level, but it is known that PS controls the magnesium/calcium balance and that the serine head is the active part of the molecule (11), so it is reasonable to assume that the serine head is in dynamic equilibrium with magnesium and calcium ions. If, however, lead ions entered the system, it would appear from the first paragraph they would bind strongly and effectively irreversibly to the serine heads, displacing both magnesium and calcium ions and blocking the cognitive processes. This seems to agree with literature from the Lead Advisory Service which quotes research work which reports that children with a blood lead reading above 15 micrograms/dL can have an IQ reduced by up to 5 units.

It would be very interesting to investigate whether lead (and cadmium) are implicated in the condition ADHD in children, as it has been shown experimentally that ADHD children behave quite normally if given phosphatidylserine(11).


  1. Lovenberg, W., Kuhn, D. M. "Role of hydroxylase cofactor in serotonin biosynthesis. Psychopharinacology Bull. 1978 Oct. 14 No.4, pp.44-46.

  2. Kuhn, D.M., O'Callaghan, J.P, Juskevich, J, Lovenberg, W. "Activation of brain tryptophan hydroxylase by ATP-Mg2+ dependence on calmadulin." Proc. Nat. Acad. Sci., Aug. 1980,17-, No.8, pp. 4688-4691.

  3. Kuhn, D.M., Vogel, Lovenberg, W. "Ca-dependent activation of tryptophan hydroxylase by ATP and Mg." Biochemical and Biophys. Res. Comm. 30 May 1978, No.2, pp. 759-766.

  4. Hamon, M., Bourgoin, S., Hery, F., Siinmonet, G. "Activation of tryptophan hydroxylase by ATP, Mg and Ca." Molecular Pharmacology, Jan. 1978, 14 No. 1, pp. 99-110.

  5. Yamaguchi, T., Fujisawa, H. "Regulation of rat brainstem tryptophan 5monooxygenase. Calciurn-dependent reversible activation by ATP and Mg." Archives of Biochemistry and Biophysics, Nov. 1979,MNo. 1, pp. 219-226.

  6. Silbergeld, E. K. (1 992). "Neurological perspective on lead toxicity" in "Human Lead Exposure" ed. H. L. Needleman, CRC Press.

  7. Matte, T. D., Landrigan, P. J. & Baker, E. L. (1992). "Occupational Lead Exposure" in "Human Lead Exposure" ed. H. L. Needleman, CRC Press.

  8. Werbach, M.F. (1997). "Foundations of nutritional medicine." Third Line press, Tarzana, California.

  9. Needleman, H. L., Riess, J. A., Tobin, M. J., Biesecker, G. E. & Greenhouse, J. B. "Bone Lead Levels and Delinquent Behavior". JAMA, Feb.7,1996,2U No.5, pp.363404.

  10. Frumkin, H. & Gerr, F. "Dimercaptosuccinic acid in the treatment of depression following lead exposure". Am. J. Ind. Med. 1993 Dec. 24: 6 pp.701-706.

  11. Parris M. Kidd, in lecture on video "Phosphatidylserine" made by Stephen Hunter Pty., Ltd., Ingleburn

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