http://www.erowid.org/re...=7064&DocPartID=6427"A contemporary investigation, utilizing modern
genetic and structural techniques, has provided a
more detailed analysis of INMT, but does not provide
a complete story. In two studies, Thompson
et al. [35,36], cloned, expressed, localized, and
characterized the activities of rabbit and human
INMT. Using Northern blot analysis, they found rabbit
INMT transcripts expressed heavily in the lung,
moderately in the liver, and weakly in the brain. Human
INMT was expressed in the lung, thyroid, adrenal
gland, heart, muscle, and spinal cord, but not in
the brain. The authors observe high Km values (an
order of magnitude higher than in previous studies
[33,34]) of TYP for recombinant human INMT and
an absence of INMT mRNA transcripts in the brain.
Thus, Thompson et al. conclude that the production
of DMT in humans is not physiologically significant.
Their conclusion places much weight on the significance
of observed Km values for recombinant human
INMT and does not take into account several
additional genetic and enzymatic concerns.
Despite years of research, there is no universally
accepted understanding of the biophysics of enzyme
function [37]; thus, the meaning of Km values,
especially for in vivo biochemical pathways,
is still open to interpretation. Although Thompson
et al. argue that high Km values signify an
enzyme–substrate combination that is not biologically
meaningful, a meta-analysis of recent research
has shown that high Km values are significant
in biological systems [38]. Although enzyme–
substrate complexes with high Km values show less
binding affinity, catalysis often proceeds at a faster
reaction rate. In fact, Ferhst [38] identifies many
enzymes in glycolysis that operate at ‘‘very high’’
Km values – showing catalytic efficiency despite
having mM affinity. Ferhst argues that affinity becomes
less important in intracellular systems
where high concentrations of necessary metabolites
are present and suggests that the specificity
constant kcat/Km is the best indicator of enzyme–
substrate efficiency. Thus, we advise against the
placement of undue emphasis on numerical values
of Km when interpreting in vitro activity. The structure
of human INMT needs to be determined and its
in vivo kinetic parameters more thoroughly assessed
before N-methylation of tryptamines can
be written off as physiologically irrelevant. The results
of Thompson et al. should also be taken with
caution because their measurements reflect the
activity of a recombinant enzyme, removed from
its natural environment where cellular compartmentalization
could significantly alter its activity.
Genetically speaking, the absence of constitutively
produced INMT transcripts in the brain does
not mean that they are never produced; many
events could potentially trigger INMT transcription
in the brain. A brief report published in 1977
claimed that INMT activity increases under stress
(electric shock and forced swim) in the rodent
brain [39]. Thus, a stress response which produces
large amounts of TYP in tissues could lead to significant
production of DMT. In addition, given the
presence of INMT transcripts in peripheral tissues,
DMT production could occur outside the brain and
still have activity in the brain because DMT can
readily cross the blood brain barrier. This would
be different from most neurotransmitters, which
do not have significant blood–brain-barrier permeability
and thus must be produced within the brain."
"Nothing is true, everything is permitted." ~ hassan i sabbah
"Experiments are the only means of attaining knowledge at our disposal. The rest is poetry, imagination." -Max Planck