Sugar Catabolism and Biosynthesis
Medical Biochemistry, Lecture 42
Lecture 42, Outline
• Examine how glucose metabolism relates to other
sugars
• Fructose metabolism and related diseases
• Galactose metabolism and related diseases
• Glucuronate metabolism and functions
• Understand nucleotide sugar interconversions
• Marks, Marks and Smith Chapter 29, primary
source, Harper’s Ch 22 secondary source. Review
Ch. 15 for sugar structural properties
UDP-Glucose Metabolism
Figure 29.4, MMS
High Energy
Phosphates
in UDP-Glucose
Metabolism
UDP-Glucose
Glycosyltranserase
Reaction
Glucuronic Acid Metabolism
Figure 29.6, MMS
Glucuronidation Reactions:
(Primarily in liver, intestine)
Bilirubin di-glucuronide
URONIC ACID
PATHWAY
Not in humans
Glucuronate derived
from breakdown of
UDP-glucuronate
(which ultimately
came from glucose
via UDP-glucose)
Alternative oxidative
pathway for glucose
Fructose Metabolism
Figure 29.2, MMS
Fructose Metabolism
- Fructose is found in foods containing sucrose (fruits), high-
fructose corn syrups, and honey.
- Dietary fructose is converted to Fructose-1-P by
fructokinase (primarily in the liver, kidney and intestine).
- Normal aldolase B function generates dihydroxyacetone
phosphate and glyceraldehyde from Fructose-1-P. The
affinity of aldolase B for fructose-1-P is much poorer than
that of fructose-1,6-biphosphate, thus fructose-1-P
accumulates in fructokinase-expressing tissues. Thus,
aldolase B is the rate-limiting enzyme for fructose
metabolism (but not glucose).
Hereditary Fructose Intolerance
- HFI results from a heriditary mutation in aldolase B that
leads to a poorly active enzyme. With aldolase B mutations,
fructose and fructose-1-P accumulate to much higher levels
for even longer periods of time, leading to inhibition of
glycogen phosphorylase. This interferes with normal
glycogenolysis and gluconeogenesis (resulting in
hypoglycemia and lactic acidosis). The F-1-P also depletes
the phosphate pools, which can affect the catabolism of
adenine nucleotides and depletion of ATP levels.
- Seen primarily in children, symptoms include diarrhea,
vomiting, failure to thrive and effects of hypoglycemia
(weakness, tremulousness, sweating) . The more dietary
fructose ingested, the more severe the symptoms.
Untreated, can result in hepatic and/or renal failure. Treated
by limiting dietary intake of fructose
Fructose and Sorbitol
Fructose can be synthesized from glucose via
aldol reductase conversion to sorbitol, and a
sorbitol dehydrogenase reaction to fructose.
This is a normal pathway in seminal vesicles,
and spermatazoa utilize fructose as a major fuel
source. In the eye, sorbitol production can be a
problem in the formation of cataracts,
especially in patients with diabetes mellitus. In
the same condition, the increased fructose and
sorbitol levels create a high osmotic pressure in
the lens. Non-enzymatic glycosylation of lens
proteins from glucose and fructose also result.
All of these cumulative effects result in the
opaque cloudiness of the lens associated with
cataracts.
Fructosuria
• Rare, but benign, genetic disorder caused by
a deficiency in fructokinase
• Why is this defect benign, as opposed to
HFI?
• Answer: no toxic fructose metabolites
accumulate, most is excreted harmlessly in
the urine
Lactose Biosynthesis
• Lactose is formed only in the mammary gland during
lactation by a two-subunit endoplasmic reticulum enzyme,
galactosyltransferase plus a modifier protein, a-
lactalbumin
a-lactalbumin is made in response to the hormone
prolactin following parturition; it lowers the Km of glucose
for galactosyltransferase from 1200 to 1 mM.
• In the absence of a-lactalbumin, galactosyltransferase
functions in glycoprotein biosynthesis pathways
Metabolism of Galactose
Figure 29.11, MMS
Galactose Metabolic Energy
Equation
More Galactose Metabolism
• How do we survive without drinking milk (the
major dietary source of galactose)? Can a new
mother who is severely lactose intolerant lactate in
the absence of dietary dairy products?
• Answer: UDP-Glc/Gal-4-Epimerase
• This enzyme facilitates galactose conversion to
Glucose-1-P, and also functions to convert glucose
metabolites to UDP-galactose for lactose synthesis
and formation of glycoproteins.
Galactosemias
• Hereditary disorders preventing the metabolism of
galactose (derived from milk/dairy lactose) into glucose
metabolites. One of the most common genetic diseases,
and frequently screened in newborns
• Result from defects in galactose 1-phosphate
uridylyltransferase or galactokinase (a milder, rarer form)
• Leads to accumulation of galactose-1-P in tissues, blood
and urine; eventually depletes liver of inorganic
phosphate, and can lead to liver failure and mental
retardation. Gal-1-P inhibits phosphoglucomutase,
leading to disregulation of UDP-glucose and UDP-
glucuronate metabolism, eventually resulting in loss of
glucuronidated bilirubin (resulting in jaundice)
Metabolic
Effects of
Gal-1-P
Accumulation
in
Galoctosemia
Galactosemias (cont.)
• In the eye lens, accumulated galactose is
converted by aldol reductase to galactitol;
contributes to cataract formation.
• In newborns, failure to thrive and
vomiting/diarrhea following milk ingestion are the
initial symptoms cataracts form and jaundice
symptoms appear within the first 2 weeks.
Diagnosed by an enzyme activity test from
erythrocytes, and controlled by galactose free diet
• In galactokinase deficiencies, Gal-1P does not
accumulate, but cataracts are still a problem
Sugar Nucleotide Conversions
Figure 29.12a, MMS
Sugar Nucleotide Conversions (cont.)
Figure 29-12b, MMS