The aldo-keto reductase (AKR) superfamily consists of over150 protein members sharing similar structure and enzymaticactivities. To date, 13 human AKRs have been identified, andthey participate in xenobiotic detoxification, biosynthesis andmetabolism. Increasing evidence suggests the involvement ofhuman AKR proteins in cancer development, progressionand treatment. Some proteins demonstrate multiple function-al features in addition to being a reductase for carbonylgroups. This review article discusses the most recent progressmade in the study of humans AKRs.

1. keto reductases: structure, substrate specificityand roles
in tumorigenesis
Abstract:
The aldo-keto reductase (AKR) superfamily consists of over150 protein members sharing
similar structure and enzymaticactivities. To date, 13 human AKRs have been identified,
andthey participate in xenobiotic detoxification, biosynthesis andmetabolism. Increasing
evidence suggests the involvement ofhuman AKR proteins in cancer development,
progressionand treatment. Some proteins demonstrate multiple function-al features in
addition to being a reductase for carbonylgroups. This review article discusses the most
recent progressmade in the study of humans AKRs.
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Introduction:
Aldo-keto reductases (AKRs) are a large group of NAD(P)H-dependent protein enzymes
with structural similarities. Theyare evolutionarily related and pervasively exist in a
widerange of organisms, from bacteria to humans (1, 2). Over 150AKRs have been identified
thus far and a web page (http://www.med.upenn.edu/akr/) supported by Dr. Penning
holdsthe most updated information on this protein superfamily.According to their sequence
homology, AKR proteins aredivided into 15 families (1, 3, 4). Proteins with more
than40% sequence identity are grouped into a family and thosesharing over 60% identity
are categorized into a subfamily.A nomenclature system of AKR proteins designates a num-
ber to identify a family, a letter to indicate a subfamily, andthen another number following
the letter to denote a uniqueprotein (4). For instance, aldo-keto reductase family 1 mem-ber
B1 (AKR1B1) indicates that this protein belongs to fam-ily 1, subfamily B of the AKR
superfamily, and it is theprotein no. 1 in the subfamily B. In addition to the desig-
nation in this nomenclature system, some proteins in theAKR superfamily have different
terms given by researchers. For example, AKR1B1 is also known as aldose
reductase(AR), and AKR1B10 is also referred to as aldose reductase-like-1 (ARL-1). Table
1summarizes the AKR proteins expres-sed in humans, which fall within three families
(AKR1,AKR6 and AKR7).AKRs are mainly cytosolic monomeric protein enzymeswith
molecular weights at 34–37 kDa. AKRs use pyridinenucleotides (NADH or NADPH) as
cofactors and catalyze ametabolic oxidation reduction, reducing carbonyl (aldehydicand
ketonic) groups into corresponding alcoholic forms.There are two exceptions for the AKR
proteins. First, not allAKR proteins are an enzyme. For instance, Rho (AKR1C10)and RhoB
crystallins (aldose reductase-related protein) aremajor components of frog and gecko lens.

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They retain aminoacid residues required for catalytic activity and bind to pyr-idine
nucleotides, but have not or very limited enzyme activ-ity towards general AKR substrates
(5, 6). Similarly, humanAKR6 proteins are channel proteins, controlling Kqion con-ductance,
but do not have enzymatic activity. Second, not allAKR proteins are monomeric. For
example, AKR6b-sub-units form a tetramer at the base of the Kqchannel, andAKR7A1
and AKR7A4 in rat form either homo- or hetero-dimers.
Substrate specificity and catalytic efficiency
Phospholipid oxidation generates several bioactive aldehydes that remain esterified to the
glycerol backbone (‘core’ aldehydes). These aldehydes induce endothelial cells to produce
monocyte chemotactic factors and enhance monocyte–endothelium adhesion. They also serve
as ligands of scavenger receptors for the uptake of oxidized lipoproteins or apoptotic cells.
The biochemical pathways involved in phospholipid aldehyde metabolism, however, remain
largely unknown. In the present study, we have examined the efficacy of the three
mammalian AKR (aldo-keto reductase) families in catalysing the reduction of phospholipid
aldehydes. The model phospholipid aldehyde POVPC [1-palmitoyl-2-(5-oxovaleroyl)-sn-
glycero-3-phosphocholine] was efficiently reduced by members of the AKR1, but not by the
AKR6 or the ARK7 family. In the AKR1 family, POVPC reductase activity was limited to
AKR1A and B. No significant activity was observed with AKR1C enzymes. Among the
active proteins, human AR (aldose reductase) (AKR1B1) showed the highest catalytic
activity. The catalytic efficiency of human small intestinal AR (AKR1B10) was comparable
with the murine AKR1B proteins 1B3 and 1B8. Among the murine proteins AKR1A4 and
AKR1B7 showed appreciably lower catalytic activity as compared with 1B3 and 1B8. The
human AKRs, 1B1 and 1B10, and the murine proteins, 1B3 and 1B8, also reduced C-7 and
C-9 sn-2 aldehydes as well as POVPE [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-
phosphoethanolamine]. AKR1A4, B1, B7 and B8 catalysed the reduction of aldehydes
generated in oxidized C16:0-20:4 phosphatidylcholine with acyl, plasmenyl or alkyl linkage
at the sn-1 position or C16:0-20:4 phosphatidylglycerol or phosphatidic acid. AKR1B1
displayed the highest activity with phosphatidic acids; AKR1A4 was more efficient with

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long-chain aldehydes such as 5-hydroxy-8-oxo-6-octenoyl derivatives, whereas AKR1B8
preferred phosphatidylglycerol. These results suggest that proteins of the AKR1A and B
families are efficient phospholipid aldehyde reductases, with non-overlapping substrate
specificity, and may be involved in tissue-specific metabolism of endogenous or dietary
phospholipid aldehydes. In human, cDNAs encoding two related liver enzymes (AKR7A2
and AKR7A3) were identified that could also reduce aflatoxin B1 dialdehyde and other
aldehyde substrates [15], [16]. The gene encoding AKR7A2 was found to be localized to
chromosome I in a region that is often missing in many human tumors [17], supporting its
role in protection against carcinogenesis. However, it has also been purified from human
brain as a succinic semialdehyde reductase [18], suggesting that it may play a role in γ-
hydroxybutyrate (GHB) biosynthesis. On the other hand, its levels appear to be elevated in
some neurodegenerative diseases such as Alzheimer's disease, supporting a role as part of a
stress response.
To understand more about the AKR7 family of enzymes, and to allow a mouse model to be
developed for investigating enzyme function, we identified a mouse liver cDNA which has
significant similarity to the rat and human AKR7 enzymes [20]. This enzyme, mouse
AKR7A5, is 78% identical to rat AKR7A1 and 89% identical to human AKR7A2. Multiple
sequence alignment of all 5 currently known AKR7 enzymes suggests that AKR7A2,
AKR7A4 and AKR7A5 are more similar to each other, and possible form a functional
equivalent grouping (Fig. 1). The affinity of the enzymes for succinic semialdehyde (SSA),
and the expression pattern of the enzymes suggests that the mouse enzyme may perform a
role more analogous to the rat AKR7A4 and human AKR7A5 enzymes than that of rat
AKR7A1 (Table 1). It is hoped that by understanding the function of the mouse enzyme it
may be possible to deduce function for the rat and human enzymes. In this paper, we have
determined the substrate specificity of the mouse enzyme and describe its inhibition by
known AKR inhibitors.
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4. Role in thermogenesis:
The rampant growth of obesity worldwide has stimulated explosive research into human
metabolism. Energy expenditure has been shown to be altered by diets differing in
macronutrient composition, with low-carbohydrate, ketogenic diets eliciting a significant
increase over other interventions. The central aim of this study was to explore the effects of
the ketone β-hydroxybutyrate (βHB) on mitochondrial bioenergetics in adipose tissue.
Methods: We employed three distinct systems—namely, cell, rodent, and human models.
Following exposure to elevated βHB, we obtained adipose tissue to quantify mitochondrial
function. Results: In every model, βHB robustly increased mitochondrial respiration,
including an increase of roughly 91% in cultured adipocytes, 113% in rodent subcutaneous
adipose tissue (SAT), and 128% in human SAT. However, this occurred without a
commensurate increase in adipose ATP production. Furthermore, in cultured adipocytes and
rodent adipose, we quantified and observed an increase in the gene expression involved in
mitochondrial biogenesis and uncoupling status following βHB exposure. Conclusions: In
conclusion, βHB increases mitochondrial respiration, but not ATP production, in mammalian
adipocytes, indicating altered mitochondrial coupling. These findings may partly explain the
increased metabolic rate evident in states of elevated ketones, and may facilitate the

5. development of novel anti-obesity interventions. We evaluated the effects of feeding a
ketogenic diet (KD) for a month on general physiology with emphasis on brown adipose
tissue (BAT) in mice. KD did not reduce the caloric intake, or weight or lipid content of
BAT. Relative epididymal fat pads were 40% greater in the mice fed the KD (P = 0.06) while
leptin was lower (P < 0.05). Blood glucose levels were 30% lower while D-β-
hydroxybutyrate levels were about 3.5-fold higher in the KD group. Plasma insulin and leptin
levels in the KD group were about half of that of the mice fed NIH-31 pellets (chow group).
Median mitochondrial size in the interscapular BAT (IBAT) of the KD group was about 60%
greater, whereas the median lipid droplet size was about half of that in the chow group.
Mitochondrial oxidative phosphorylation proteins were increased (1.5-3-fold) and the
uncoupling protein 1 levels were increased by threefold in mice fed the KD. The levels of
PPARγ, PGC-1α, and Sirt1 in KD group were 1.5-3-fold while level of Sirt3 was about half
of that in the chow-fed group. IBAT cyclic AMP levels were 60% higher in the KD group
and cAMP response element binding protein was 2.5-fold higher, suggesting increased
sympathetic system activity.
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Thermogenic properties:

6. 7-keto-DHEA is produced naturally in your body from dehydroepiandrosterone (DHEA), a
hormone that comes from the adrenal glands located on top of each of your kidneys.
DHEA is one of the most abundant circulating steroid hormones in your body. It functions as
a precursor for the male and female sex hormones, including testosterone and estrogen
(1Trusted Source).
But unlike DHEA, 7-keto-DHEA does not actively interact with the sex hormones.
Therefore, when taken as an oral supplement, it does not increase the amount of them in your
blood (2Trusted Source).
Early studies have suggested that DHEA prevents fat gain in mice due to its thermogenic, or
heat-producing, properties (3Trusted Source, 4Trusted Source, 5Trusted Source, 6Trusted
Source). Thermogenesis is the process by which your body burns calories to produce heat.
One test-tube study found that 7-keto-DHEA was two-and-a-half times more thermogenic
than its parent compound DHEA (7Trusted Source).
This finding led researchers to begin testing the thermogenic properties of 7-keto-DHEA in
humans.

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May Increase Your Metabolism
To date, only two studies have looked at the effects of 7-Keto on metabolism.
In the first study, researchers randomized people who were overweight to receive a
supplement containing 100 mg of 7-Keto or a placebo for eight weeks.
While the group receiving the 7-Keto supplement lost significantly more weight than those
given a placebo, there was no difference in basal metabolic rate (BMR) between the two
groups.
Basal metabolic rate is the number of calories your body needs to perform basic functions
that sustain life, such as breathing and circulating blood.
However, in another study, 7-Keto was found to increase the resting metabolic rate (RMR) of
people who were overweight. RMR is less accurate than BMR at estimating the number of
calories your body needs to sustain life, but it’s still a useful measure of metabolism.
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The study found that 7-Keto not only prevented the decrease in metabolism that’s normally
associated with a reduced-calorie diet but also increased metabolism by 1.4% above baseline.
Conclusion:
Fatty acid oxidation product, acetyl-CoA is the substrate for ketogenesis and the first step
involves condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA in the
reaction catalyzed by acetoacetyl-CoA thiolase. Ketones are formed when there is not
enough sugar or glucose to supply the body's fuel needs. This occurs overnight, and
during dieting or fasting. During these periods, insulin levels are low, but glucagon and

8. epinephrine levels are relatively normal. Ketone bodies are metabolites that replace glucose
as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting,
extenuating exercise, or pathological conditions such as diabetes.
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