Metabolism of Some Individual Amino Acids
of collagen (Chapter 25). Hydroxyproline released by
that of proline. Hydroxyproline cleavage initiated by
hydroxyproline oxidase eventually yields glyoxylate and
type I, proline oxidase
is deficient, and in type II, A'-pyrroline-5-carboxylate
dehydrogenase is deficient.
from hydroxyproline oxidase deficiency. All are clinically
harmless autosomal recessive traits.
essential for growth in
children. Histidine is synthesized from 5-phosphoribosyl-
1-pyrophosphate and ATP, forming N'-T-phosphoribosyl-
ATP, catalyzed by the allosteric enzyme ATP phosphori-
bosyltransferase. This reaction is analogous to the initial
reaction of purine nucleotide biosynthesis (Chapter 27).
Histamine breakdown produces a one-carbon unit (N5-
formiminotetrahydrofolate) and glutamate (Figure 17-13)
by a nonoxidative deamination to urocanate, cleavage of
the imidazole ring to N-formiminoglutamate (Figlu), and
transfer of the formimino group (-CH=NH) to tetrahy-
drofolate (Chapter 27).
Folate deficiency leads to accumulation of Figlu, which
is excreted in urine. The excretion is very pronounced
after a loading dose of histidine, a test used to detect fo-
late deficiency. More sensitive radioisotopic assays use fo-
late binders to the vitamins. High urinary levels of
may coexist with elevated levels of serum folate. Thus, in
vitamin Bn (
) deficiency, since cobalamin
participates in the following reaction, FH4 is trapped as
CH — CH— c o o ~
CH =CH CO O
0 — C
— CH— CH p O C T
— C— CH— CRCH CO Cr
Catabolism of histidine.
N5-methyltetrahydrofolate and is unavailable as a carrier
for the formimino group of Figlu.
Similarly, a deficiency of glutamate formiminotransferase
leads to accumulation of Figlu and high levels of serum
ammonia-lyase. With a normal diet, histidine (and the pro-
ducts imidazole-pyruvate, imidazole-lactate, imidazole-
acetate) accumulates in plasma, cerebrospinal fluid, and
urine. This rare autosomal recessive disease may be
benign or may manifest with mental retardation and speech
and /3-alanine yield the dipeptide carnosine
(present in muscle), and histidine and y-aminobutyrate
yield homocamosine (found in brain). Methylhistidyl resi-
dues are found in some proteins (e.g., actin; Chapter 21)
as a result of posttranslational modification.
C H 2— C — N H 3 +
C 0 0 ~
C H 2— C H 2— N H 3+
. . .
Histamine occurs in blood basophils, tissue mast cells,
and certain cells of the gastric mucosa and other parts of
the body (e.g., anterior and posterior lobes of the pituitary,
some areas of the brain). Histamine is a neurotransmitter in
certain nerves (“histaminergic”) in the brain. In mast cells
found in loose connective tissue and capsules, especially
around blood vessels, and in basophils, histamine is stored
in granules bound by ionic interactions to a heparin-protein
complex and is released (by degranulation, vacuoliza-
tion, and depletion) in immediate hypersensitivity reac-
tions, trauma, and nonspecific injuries (infection, burns).
Degranulation is affected by oxygen, temperature, and
metabolic inhibitors. Release of histamine from gastric
mucosal cells is mediated by acetylcholine (released by
parasympathetic nerve stimulation) and gastrin and stim-
ulates secretion of hydrochloric acid (Chapter 12). His-
tamine causes contraction of smooth muscle in various
organs (gut, bronchi) by binding to Hi receptors. The
conventional antihistaminic drugs (e.g., diphenhydramine
and pyrilamine) are Hi-receptor antagonists and are use-
ful in the management of various allergic manifestations.
However, in acute anaphylaxis, bronchiolar constriction is
rapidly relieved by epinephrine (a physiological antagonist