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Chapter 28
Chapter 28
PROTEIN TURNOVER
The continuous degradation and synthesis (turnover) of cellular proteins
occur in all forms of life.
Each day, humans turn over 1% to 2% of their total body
protein, principally muscle protein.
High rates of protein degradation occur in tissues that are
undergoing structural rearrangement, for example:
uterine tissue during pregnancy
skeletal muscle in starvation
tadpole tail tissue during metamorphosis
While approximately 75% of the amino acids liberated by
protein degradation are reutilized, the remaining excess free
amino acids are not stored for future use.
Amino acids not immediately incorporated into new protein are
rapidly degraded.
The major portion of the carbon skeletons of the amino acids
is converted to amphibolic intermediates, while in humans the
amino nitrogen is converted to urea and excreted in the urine.
ATP-Independent Degradation
Degradation of blood glycoproteins follows loss of a sialic acid
moiety from the nonreducing ends of their oligosaccharide
chains.
Asialoglycoproteins are then internalized by liver-cell
asialoglycoprotein receptors and degraded by lysosomal
proteases.
Extracellular, membrane-associated, and long-lived
intracellular proteins are also degraded in lysosomes by ATP-
independent processes.
N-Acetylglutamate Synthase
Urea cycle disorders are characterized by: N-ACETYLGLUTAMATE SYNTHASE, EC 2.3.1.1 (NAGS):
Hyperammonemia catalyzes the formation from acetyl-CoA and glutamate
Encephalopathy of the N-acetylglutamate essential for carbamoyl
Respiratory alkalosis phosphate synthase I activity.
Four of the five metabolic diseases, deficiencies of carbamoyl l-Glutamate + acetyl-CoA N-acetyl-l-glutamate + CoASH
phosphate synthase I, ornithine carbamoyl transferase, While the clinical and biochemical features of NAGS
argininosuccinate synthase, and argininosuccinate lyase, result deficiency are indistinguishable from those arising from a
in the accumulation of precursors of urea, principally ammonia defect in carbamoyl phosphate synthase I, a deficiency in
and glutamine. NAGS may respond to administered N-acetylglutamate.
Ammonia intoxication is most severe when the metabolic block
occurs at reactions 1 or 2, for if citrulline can be synthesized, Ornithine Permease
some ammonia has already been removed by being covalently HHH SYNDROME:
linked to an organic metabolite. The hyperornithinemia, hyperammonemia, and
homocitrullinuria syndrome.
results from mutation of the ORNT1 gene:
encodes the mitochondrial membrane ornithine
permease
Argininosuccinate Synthase CAN GENE THERAPY OFFER PROMISE FOR CORRECTING DEFECTS
In addition to patients who lack detectable argininosuccinate IN UREA BIOSYNTHESIS?
synthase activity: Gene therapy of defects in the enzymes of the urea cycle is
a 25-fold elevated Km for citrulline has been reported an area of active investigation.
In the resulting citrullinemia: Despite encouraging results in animal models using an
plasma and cerebrospinal fluid citrulline levels are elevated adenoviral vector to treat citrullinemia, at present gene
1 to 2 g of citrulline are excreted daily therapy provides no effective solution for human subjects.
SUMMARY
Human subjects degrade 1% to 2% of their body protein daily at
rates that vary widely between proteins and with physiologic state. Key
Argininosuccinate Lyase regulatory enzymes often have short half-lives.
ARGININOSUCCINIC ACIDURIA: Proteins are degraded by both ATP-dependent and ATP independent
accompanied by elevated levels of argininosuccinate in pathways. Ubiquitin targets many intracellular proteins for degradation.
blood, cerebrospinal fluid urine Liver cell surface receptors bind and internalize circulating
associated with friable, tufted hair (trichorrhexis asialoglycoproteins destined for lysosomal degradation.
nodosa) Polyubiquitinated proteins are degraded by proteases on the inner
Both early- and late-onset types are known. surface of a cylindrical macromolecule, the proteasome. Entry into the
The metabolic defect is in argininosuccinate lyase proteasome is gated by a donut-shaped protein pore that rejects entry
Diagnosis by the measurement of erythrocyte to all but polyubiquitinated proteins.
argininosuccinate lyase activity can be performed on Fish excrete highly toxic NH3 directly. Birds convert NH3 to uric
umbilical cord blood or amniotic fluid cells. acid. Higher vertebrates convert NH3 to urea.
Transamination channels amino acid nitrogen into glutamate. GDH
Arginase occupies a central position in nitrogen metabolism.
HYPERARGININEMIA: Glutamine synthase converts NH3 to nontoxic glutamine. Glutaminase
an autosomal recessive defect in the gene for arginase releases NH3 for use in urea synthesis.
the first symptoms of hyperargininemia typically do not NH3, CO2, and the amide nitrogen of aspartate provide the atoms of
appear until age 2 to 4 years urea.
Blood and cerebrospinal fluid levels of arginine are Hepatic urea synthesis takes place in part in the mitochondrial
elevated. matrix and in part in the cytosol.
The urinary amino acid pattern, which resembles that of Changes in enzyme levels and allosteric regulation of carbamoyl
lysine-cystinuria, may reflect competition by arginine phosphate synthase I by N-acetylglutamate regulate urea biosynthesis.
with lysine and cysteine for reabsorption in the renal Metabolic diseases are associated with defects in each enzyme of
tubule. the urea cycle, of the membrane-associated ornithine permease, and of
NAGS.
ANALYSIS OF NEONATE BLOOD BY TANDEM MASS The metabolic disorders of urea biosynthesis illustrate six general
SPECTROMETRY CAN DETECT METABOLIC DISEASES principles of all metabolic disorders.
Metabolic diseases caused by the absence or functional Tandem mass spectrometry is the technique of choice for screening
impairment of metabolic enzymes can be devastating. neonates for inherited metabolic diseases.