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Karl Anker Jørgensen

Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis

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The a-oxoaldehyde methylglyoxal is a ubiquitous
and highly reactive metabolite known to be involved
in aging- and diabetes-related diseases. If not
detoxified by the endogenous glyoxalase system,
it exerts its detrimental effects primarily by reacting
with biopolymers such as DNA and proteins. We
now demonstrate that during ketosis, another meta-
bolic route is operative via direct non-enzymatic
aldol reaction between methylglyoxal and the ke-
tone body acetoacetate, leading to 3-hydroxyhex-
ane-2,5-dione. This novel metabolite is present at
a concentration of 10%–20% of the methylglyoxal
level in the blood of insulin-starved patients. By em-
ploying a metabolite-alkyne-tagging strategy it is
clarified that 3-hydroxyhexane-2,5-dione is further
metabolized to non-glycating species in human
blood. The discovery represents a new direction
within non-enzymatic metabolism and within the
use of alkyne-tagging for metabolism studies and
it revitalizes acetoacetate as a competent endoge-
nous carbon nucleophile.
Original languageDanish
JournalCell Chemical Biology
Pages (from-to)935-943
Number of pages9
Publication statusPublished - 2017

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