Lactose Synthesis
by D. DeWitt, PhD
v1.1 10/15/07
A. Introduction
Although it might seem straight forward, the synthesis of lactose,
either
as a simple condensation reaction (a.k.a. dehydration
synthesis), or
what actually happens in mammary glands is
complicated.
Before we explore lactose's creation, let's take a look at its
structure. In Figure 1, the space-filling model is pretty but
rather difficult to understand.
In
Figure 2, you will find the structural
formula for a lactose. It is a disaccharide made from
the simple sugars galactose (on the left) and glucose (on the
right).
I will
caution you right now that there are many different views of
lactose on the internet, so if this one does not agree with your
impression, there are reasons: 1) errors (e.g., lactose
has 12 oxygens) and 2) synthesis from different forms (isomers) of
galactose and glucose.
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Figure 1: Space-filling
Model of Lactose
(Click on image to visit originating
website.)
Figure 2: Structural Model of Lactose
Note: Carbon atoms are assumed at all angles of each geometric shape
(hexagons) unless an atom is shown (e.g. oxygen)
(Click on image to visit
originating website. I corrected their diagram.)
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The first issue is the
process by which two sugars can be chemically joined.
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The answer is found in the fact
that these sugars are literally covered
with hydroxyl (-OH) groups. As shown in Figure 3 on the right, a
hydroxyl
group on one sugar (-OH) can be connected to another
hydroxyl group (HO) on a second sugar by removing
an -OH from the first sugar and a H- from the second leaving a -O-
bond connecting the two sugars in a disaccharide.
In addition, the released -OH and H- join to form H2O (HOH). The name of the -O- bond
is called a glycosidic bond. The bond gets its
name from the fact that the disaccharide is also called a glycoside.
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sugar1-OH
+ HO-sugar2
sugar1- + -O-sugar2 + -OH + H-
sugar1-O-sugar2 + HOH
Figure 3: Glycosidic Bond
Formation
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The overall reaction is called
either a) a condensation reaction
because water appears, or b) a dehydration
synthesis because
water is removed (dehydration). Therefore the formation of the
disaccharide lactose occurs via a condensation reaction. Because
it occurs within cells, the reaction occurs only with the aide
of an enzyme.
ACTUALLY... in mammary gland cells, it occurs
differently, but I will address the real world later in this discussion.
Let's take a closer look at the specifics (and therefore, the sources
of confusion) about condensation reactions.
Monosaccharide ISOMERS
Two molecules are isomers if they have the same molecular formula, but
different structural formulas. Therefore galactose and glucose
are structural isomers because they both have the same
molecular formula of C6H12O6but
they are arranged differently. (E.g., Galactose and glucose
differ at carbon 1 sometimes, and always at carbon 4.) In Figure
4 below, you can see how
galactose and glucose carbons are numbered. Reference to carbons
1 and 4 will be forthcoming. |
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Figure 4: The Aldohexoses
Galactose (left)
and Glucose
(right)
(Click on image to visit
originating website.)
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With
each named monosaccharide, alternative forms exist as well. These
are also isomers, based on more subtle differences. Examples are D
and L isomers and more
useful to this discussion, alpha and beta isomers (a.k.a., anomers).
THE major source of confusion and the source of
the abundance of alternate structures
for lactose, is the lack of attention to alternate forms (a.k.a.
isomers) of the
building block monosaccharides galactose and glucose.
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Alpha and Beta Isomers
(a.k.a., alpha and beta anomers)
If you examine Figure 4 above, and find the Oxygen atom in each ring,
you will find a carbon to the right in the ring, denoted as carbon
1. This carbon is called the anomeric
carbon.
So normally, a glycosidic bond is made between the -OH of an anomeric
carbon of one monosaccharide and an -OH connected to any carbon in the
second monosaccharide. The glycosidic bonds of interest in my
courses, are 1-->4, 1-->6, 1-->2, 1-->1.
Anomeric forms of glucose
In Figure 5 below, you can see that the anomeric forms of glucose
differ ONLY at the anomeric carbon #1. When the hydroxyl group is
found below carbon 1, it is called the alpha anomer.
When the hydroxyl group is above carbon 1, it is called the beta
anomer.
Note: Sometimes they are just called alpha and beta isomers of
glucose. In some of my course discussions (A&P), I also refer
to this as "alpha and beta-ness"... to avoid annoying my students with
ANOTHER confusing term. In Mol. Bio. and Bio. Chem., I DO refer
to anomeric isomers.
Figure 5: Alpha-glucose
(left) and Geta-glucose (right)
(Click on image to visit
originating website.)
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Let's make disaccharides using
just alpha and beta glucoses.
An classic example of how important the correct
use of alpha and beta forms of glucose is, is the difference in
disaccharides (and polysaccharides) produced using only alpha-glucose
or only beta-glucose.
Alpha-glucose oligomers and polymers
As shown below in Figure 6, if you join two alpha-glucoses together you
form the disaccharide alpha-maltose, and it is linked via an alpha-1,4-glycosidic
bond. It is called alpha-maltose because the "free anomeric
carbon" (i.e., the carbon 1 on the right side of maltose), is in the
alpha form.
Figure 6: Alpha-maltose
Synthesis from Two Alpha-glucoses
(Click on image to visit
originating website.)
If you
used one
alpha-glucose on the left, and one beta-glucose on the right, you would
end up with a maltose, called beta-maltose, because the "free anomeric
carbon" (i.e., the carbon 1 on the right side of maltose), is in the
beta form.
If you
continue this process to make a polysaccharide, you end up with the
starch amylose. Note
also that you can eat and digest maltose or amylose and gain valuable
energy by absorbing the resultant alpha-glucoses into your blood.
Beta-glucose oligomers and polymers
As
shown below in Figure 7, if you join two beta-glucoses
together you form the disaccharide cellobiose, and it is
linked via a beta-1,4-glycosidic bond. If you continue
this
process to make a
polysaccharide, you
end up with the cellulose.
Figure 7: Cellbiose
Synthesis from Two Beta-glucoses
(Click on image to visit
originating website.)
Note
also that you CAN eat, but you CAN NOT digest cellobiose or
cellulose.
Therefore, you will NOT gain valuable
energy from this meal. Why not? Because your digestive
system does
not make the necessary enzyme cellobiase or cellulase that will break
beta-1,4-glycosidic bonds.
And so... such as small difference between alpha and beta isomers of
glucose, changes life on earth! What would life be like if all
animals could digest beta bonds?
One more thing about beta bonds...
As you can see in Figure 7, if you were to synthesize a long polymer of
beta-glucoses, the string would move upward at an angle.. which takes
up a lot of space on paper..... so there are other ways to show the
molecule that keep it horizontal.
In Figure 8, the "zig-zag" method shows a section of cellulose with ...
used to show that the molecule extends with many more glucoses.
Figure 8: Cellulose
"zig-zag" Representation of the Glycosidic Bonds
(Click on image to visit
originating website.)
In
Figure 9, another method shows alternating upside down glucoses.
In addition, this version shows the ends, and indicates MANY monomers
by bracketing the repeating cellobiose dimer.
Figure 9: Cellulose
"alternating UPSIDE DOWN" Representation of the Glycosidic Bonds
(Click on image to visit
originating website.)
And... now you are educated to the level that will allow for an
easy discussion of lactose synthesis.
Anomeric forms of galactose
In Figure 10 below, you can see that the anomeric forms of galactose
differ ONLY
at the anomeric carbon #1. When the hydroxyl group is found below
carbon 1, it is called the alpha anomer. When the hydroxyl group
is
above carbon 1, it is called the beta anomer.
Figure 10: Alpha and Beta Anomers of
Galactose
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It is now time to
synthesize lactose!
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B. Lactose Synthesis
by Condensation Reaction (a.k.a., Dehydration
Synthesis)
Now
that you understand that galactose and glucose are available in
anomeric
forms, the obvious
question is: Is lactose made from alpha or beta
galactose and alpha or beta glucose?
If
we examine lactose, maybe we can figure it out.
Figure
11: Structural Model of Lactose
(Click on image to visit
originating website.)
In Figure 11, the galactose on
the
left appears to be a beta-galactose because a -H (at *1) is below carbon 1... which means
it had a -OH above, before the condensation reaction ran.
On the far right in Figure 11, there is an -OH...at *2 below carbon 1 so it was made
from alpha glucose.
So are we done?
NOPE!
If you run an image search in Google on the internet,
you will find several different looking versions of lactose. Are
they all errors if they do not look like Figure 11 or Figure 2?
The problem is that you COULD make lactose with alpha or beta
galactose, and alpha or beta glucose.
So what is the answer? What form of lactose is
really the important one for my biology courses?
I have not been able to find any reference that states which one is the
predominant form found in milk. However, it is probably time to look at
how mammary glands produce lactose. Perhaps some insight can be
gleaned from the way female mammals make lactose.
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| And now for the real way
lactose is made in mammary gland cells! |
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C. Lactose Synthesis
in Mammary Glands
Lactose
is made ONLY inside the Golgi organelle inside mammary gland
cells. It is the major carbohydrate of milk.
Below, you
will see the chemical reaction that mammals use to make lactose.
UDP-Galactose + Glucose
-------> Lactose
Figure 16: Synthesis of Lactose
within Mammary Gland Golgi Organelle
Abbreviations: GT = galactosyltransferase;
alpha-LA = alpha-lactalbumin;
NDPase = nucleotide diphosphatase;
Pi = inorganic phosphate;
UDP-galactose = uridine diphosphate galactose;
UMP = uridine monophosphate
(Ref: Modified by D.
DeWitt)
(Click
on image to visit
originating website.)
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Obviously an enzyme is needed to
do this. Then enzyme is known as lactose synthase
(or lactose synthetase). Actually, lactose synthase
is made of two components:
1) a protein called alpha-lactalbumin,
and
2) an enzyme called galactosyltransferase.
If you
search for this enzyme on the internet using Google or Yahoo, you will
find that it is more accurately called ß1,4
Galactosyltransferase.
The beta (ß), means that it uses
beta-galactose and makes a beta-glycosidic bond between galactose and
glucose.
So..... lactose must be either:
1.
beta-galactose-alpha glucose
or
2.
beta-galactose-beta glucose.
If you want to learn more about the details of lactose synthesis in
mammary gland cells, or in mammals in general, please click on Figure
16 to visit an interesting website.
Back to the mystery of lactose chemical
structure.
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So.....
to the best of my knowledge that I have
been
able to garner from textbooks and the internet, lactose, is made from
beta-galactose and connected via a beta 1-->4 glycosidic bond to
either alpha- or beta-glucose.
According to a Biochemistry,
2nd ed. by Moran, Schrimgeour, Horton, Ochs and Rawn, the lactose found
in milk ranges in concentration from 2% to 9% and is Beta-lactose as
shown in figure 18.
If anyone finds more information
please contact me at:
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Figure
17: Structural Model of an Alpha-lactose
made with a beta-glycosidic bond connecting beta-galactose to
alpha-glucose
Figure
18: Structural Model of a Beta-lactose
made with a beta-glycosidic bond connecting beta-galactose
to beta-glucose
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Figure 14: Structural Model of a Beta-lactose