From the Archives: Bernhard Witkop (left, the author) receives the Hillebrand Award on March 12, 1959, from American Chemical Society past president Joseph Spies (center). Sidney Udenfriend (right) also a Hillebrand awardee, delivered that year’s Hillebrand lecture, in which he emphasized the growing links between chemistry and psychiatry with the uncovering of the metabolism of the amino acids tryptophan, phenylalanine, tyrosine, dopa, and histidine.

On May 25, friends, disciples, and colleagues of Sidney Udenfriend will gather at Drew University in Madison, N.J., for a memorial to a pioneer in the fields of metabolism and molecular biology.

When James Shannon hired both of us more than 50 years ago to work in the new National Heart Institute, he predicted that our common interests would lead to a successful marriage of organic chemistry and biochemistry. Indeed, our mutual "trypto-fun" started when, in 1953, Udenfriend and Herb Weissbach demonstrated that l-5-hydroxytryptophan is the natural substrate for aromatic amino acid decarboxylase and converts it to serotonin. At that time, serotonin was suspected to be a novel neurotransmitter, controlling sleep, memory, mood, and other physiological functions. This area of budding research would ultimately lead to the organization of ISTRY—the International Study Group for Tryptophan Research—in 1983.

Tryptophan-5-hydroxylase was another of Udenfriend’s studied enzymes. He wanted to assay it by a tritiated substrate in the same way he’d followed the conversion of trans-4-3H-l-proline to 4-OH-proline in the post-translational conversion of procollagen to collagen. However, there was a big surprise, in 1966, when the conversion of 5-3H-tryptophan to 5-OH-tryptophan proceeded with almost full retention of tritium, which was not lost but migrated into the neighboring 4-position. In fairness to all the participating investigators, Udenfriend coined the name of "NIH-Shift" for this unprecedented phenomenon.

The biosynthesis and metabolism of another fundamental neurotransmitter, norepinephrine, fascinated both Udenfriend and Julius Axelrod, who received the Nobel Prize in 1970 for related research. In the formation of norepinephrine, according to Udenfriend, the rate-limiting step is hydroxylation of tyrosine. The preceding step, hydroxylation of phenylalanine, is involved in the clinical syndrome of phenylpyruvic oligophrenia, or phenylketonuria. Again, when Udenfriend looked for a rapid assay of phenylalanine hydroxylase by offering it the tritiated substrate 4-3H-l-phenylalanine, tyrosine was formed with more than 95 percent retention of tritium.

The introduction of the "Visiting Program" in the late fifties was a boon for NIH and brought us such outstanding postdocs as Siro Senoh, from Japan, who made 6-hydroxydopamine available to Udenfriend and the novel metabolite of norepinephrine, the so-called normetanephrine, available to Axelrod.

When in 1968 Udenfriend accepted the position of director of the Roche Institute for Molecular Biology, he parted from his beloved NIH with a heavy heart. Soon thereafter, he showed his gratitude and attachment by acting as one of the three "godfathers" who helped to name Building 1 the James Augustin Shannon Building.

A less well-known contribution of Udenfriend to NIH was his early recognition of the merits of Marshall Nirenberg, years before Nirenberg received the Nobel Prize in 1968 for deciphering the genetic code, and of Nirenberg’s wife, Brazilian biochemist Perola Zaltzman, who worked in Udenfriend’s lab and would have left had her husband concluded his search for a position outside NIH. If not for Udenfriend’s finding places for Nirenberg and Zaltzman at the Heart Institute, NIH would have lost them both.

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