section 17.3
Metabolism of Some Individual Amino Acids
347
Phosphocreatine
i
Creatinine
F IG U R E 1 7 -1 0
Overview of glycine and serine metabolism.
These kinases phosphorylate specific proteins that may
be involved in removal or sequestration of Ca2+ or other
ions, resulting in physiological stimuli. The physiologi-
cal actions of cGMP are terminated by its conversion to
5'-GMP by cGMP-phosphodiesterase. Inhibitors of cGMP
phosphodiesterase promote the actions of NO.
Sildenafil
is a selective inhibitor of a specific cGMP
phosphodiesterase (type 5) present in the corpus caver-
nosum. This compound (structure shown in Figure 17-9)
is used orally in the therapy of some types of
erectile dys-
function.
NO is the principal transmitter involved in the
relaxation of penile smooth muscle. During central or re-
flex sexual arousal, NO production is enhanced leading
to increased production of cGMP. Smooth muscle relax-
ation permits the corpus cavemosum to fill with blood.
Since the therapeutic effect of sildenafil potentiates the
action of cGMP, the drug is ineffective in the absence of
sexual arousal. The relaxation of cavernosal smooth mus-
cle caused by cGMP involves inhibition of Ca2+ uptake.
Prostaglandin Ei (alprostadil) inhibits the uptake of Ca2+
smooth muscle by a separate mechanism and causes erec-
tions in the absence of sexual arousal. Blood flow through
corpus cavernosum may also be increased by a-adrenergic
blocking agents (e.g., phentolamine mesylate). Coadmin-
istration of NO donor drugs with the NO potentiation drug
sildenafil may have severe consequences on the cardiovas-
cular system.
Signal transduction of NO by cGMP-independent
mechanisms include ADP-ribosylation of glyceraldehyde-
3-phosphate dehydrogenase (GADPH), an enzyme of the
glycolytic pathway (Chapter 13), and interactions with
many heme-containing and nonheme iron-sulfur contain-
ing proteins. NO activates ADP-ribosyltransferase which
catalyzes the transfer of ADP-ribose from NAD
to
GADPH. This results in the inactivation of GADPH caus-
ing inhibition of glycolysis and decreased ATP production.
The antiaggregability of platelets and the neurotoxicity of
NO have been attributed to inhibition of glycolysis by NO.
Glycine
Glycine
participates in a number of synthetic path-
ways and is oxidized to provide energy (Figure 17-10).
The interconversion of glycine and serine by serine
hydroxymethyltransferase is shown below:
pyridoxal phosphate
NH+-CH2-COCT + N
5
,N
10
-methylene-FH
4
+ H20 <
>
glycine
HOH
2
C-CHNH+-COO~ + f h
4
serine
The one-carbon carrier N5,N10-methylenetetrahydrofolate
is derived from reactions of the one-carbon pool (Chap-
ter
27).
[The
term
one-carbon pool
refers
to
all
single-carbon-containing metabolites (e.g., -CH3, -CHO,
NH=C-, etc.) that can be utilized in biosynthetic reac-
tions such as formation of purine and pyrimidine.] These
reactions include oxidation of glycine by glycine cleavage
enzyme complex (glycine synthase):
pyridoxal phosphate
NHj-CHo-COO
+ FH4 + NAD+ <
>:
glycine
NH+ + C 02 + NADH + N5 ,N10-methylene-FH4
This reaction favors glycine degradation, but the formation
of glycine may also occur. The enzyme complex is mito-
chondrial and contains a pyridoxal phosphate-dependent
glycine decarboxylase, a lipoic acid-containing pro-
tein that is a carrier of an aminomethyl moiety,
a
tetrahydrofolate-requiring
enzyme,
and
lipoamide
dehydrogenase. The reactions of glycine cleavage re-
semble those of oxidative decarboxylation of pyruvate
(Chapter 13).
